Ergoline compounds and uses thereof

ABSTRACT

Provided herein are ergoline compounds and pharmaceutical compositions thereof. In some embodiments, provided herein are methods of treatment, prevention, or amelioration of a variety of medical disorders such as, for example, migraine using the compounds and pharmaceutical compositions disclosed herein. In still other embodiments, provided herein are methods of agonizing receptors such as, for example, the 5-HT 1A , 5-HT 1B  and 5-HT 1D  receptors without agonizing the 5-HT 2B  receptor using the compounds and pharmaceutical compositions disclosed herein. In still other embodiments, provided herein are methods of antagonizing the 5-HT 2B  adrenergic alpha 2A  and/or the alpha 2B  receptors using the compounds and pharmaceutical compositions disclosed herein. In still other embodiments, provided herein are methods of antagonizing the D2 and D3 receptor using the compounds and pharmaceutical compositions disclosed herein.

This application claims priority under 35 U.S.C. §119 (e) from U.S.Provisional Application Ser. No. 62/105,208 filed Jan. 20, 2015, whichis hereby incorporated by reference in its entirety.

FIELD

Provided herein are ergoline compounds and pharmaceutical compositionsthereof. In some embodiments, provided herein are methods of treatment,prevention, or amelioration of a variety of medical disorders such as,for example, migraine using the compounds and pharmaceuticalcompositions disclosed herein. In other embodiments, provided herein aremethods of agonizing receptors such as, for example, the 5-HT_(1A),5-HT_(1B) and 5-HT_(1D) receptors without agonizing the 5-HT_(2B)receptor using the compounds and pharmaceutical compositions disclosedherein. In still other embodiments, provided herein are methods ofantagonizing the 5-HT_(2B), adrenergic alpha_(2A) and/or the alpha_(2B)receptors using the compounds and pharmaceutical compositions disclosedherein. In still other embodiments, provided herein are methods ofantagonizing the D2 and D3 receptor using the compounds andpharmaceutical compositions disclosed herein.

BACKGROUND

Many naturally occurring and synthetic ergolines are known to bind in toneurotransmitter receptors, such as, for example, dopamine,noradrenaline and serotonin receptors and to function as unselectiveagonists or antagonists at these receptors. Compounds that are selectiveor specific for certain specific receptors may lead to desirabletherapeutic actions while eliminating or reducing unwanted side effects.For example, selective serotonin antagonists have been developed for thetreatment of migraine and more recently, selective dopamine agonists forthe treatment of Parkinson's disease and hyperprolactinemia have beendiscovered.

However, there is a continuing need for less toxic ergoline derivativesto treat a variety of disorders such as, for example, migraines whereinselective agonism (e.g., 5-HT_(1D) and 5-HT₁) and antagonism (e.g.,5-HT_(2B)) on multiple neurotransmitters receptors achieved by a singlecompound is desirable.

SUMMARY

Provided herein are ergoline compounds which address these and otherneeds. In one aspect, the ergoline compounds described herein includecompounds of structural Formula (I):

or polymorphs, salts, hydrates or solvates thereof, wherein: R₁ ishydrogen, alkyl, substituted alkyl, heteroalkyl, substitutedheteroalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,halo, haloalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,substituted

heteroarylalkyl, —S(O)_(j)R₁₀₁, —C(O)NR₁₀₂R₁₀₃ or —CO₂R₁₀₄; R₂ is alkyl,substituted alkyl, acyl, substituted acyl, halo, haloalkyl, heteroalkyl,substituted heteroalkyl, arylalkyl, substituted arylalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl, substitutedheteroarylalkyl, —NO₂, —N₃, —S(O)_(k)R₁₁₀, —OR₁₁₁, —NR₁₁₂R₁₁₃,—C(O)NR₁₁₄R₁₁₅, —OC(O)NR₁₁₆R₁₁₇, —CO₂R₁₁₈ or —OC(O)R₁₁₉; n is 0, 1, 2 or3; R₃ is hydrogen, alkyl, substituted alkyl, haloalkyl, heteroalkyl,substituted heteroalkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl orsubstituted heteroarylalkyl; R₄ and R₅ are independently hydrogen,alkyl, substituted alkyl, halo,haloalkyl, —OR₁₂₀, —OC(O)NR₁₂₁R₁₂₂, —OC(O)R₁₂₃ or together with theatoms to which they are attached form a double bond; R₆ and R₇ areindependently hydrogen, acyl, subsisted acyl, alkyl, substituted alkyl,haloalkyl, heteroalkyl or substituted heteroalkyl; X is —S—, —SO₂— or—NR₈—; Z is —CH₂— or —NR₉—; a is 0 or 1; R₈, R₉, R₁₀₂-R₁₀₄ and R₁₁₁-R₁₂₃are independently hydrogen, alkyl, substituted alkyl, acyl, substitutedacyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,haloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl or substituted heteroarylalkyl; R₁₀₁ andR₁₁₀ are independently alkyl, substituted alkyl, acyl, substituted acyl,aryl, substituted aryl, arylalkyl, substituted arylalkyl, halo,haloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl or substituted heteroarylalkyl; andoptionally, R₁ and R₈ along with the atoms to which they are attachedform a 5, 6 or 7 membered ring.

Also provided are derivatives, including salts, esters, enol ethers,enol esters, solvates, hydrates, metabolites and prodrugs of thecompounds described herein. Further provided are compositions, whichinclude the compounds provided herein and a vehicle.

Methods of treating, preventing, or ameliorating symptoms of medicaldisorders such as, for example, migraine, migraine, ALS, Alzheimer'sdisease, Parkinson's disease, extra-pyramidal disorders, depression,nausea, emesis, restless legs syndrome, insomnia, aggression,Huntington's disease, cardiopulmonary disease, fibrogenesis, pulmonaryarterial hypertension, anxiety, drug addictions, dystonia, parasomnia orhyperprolactinemia are also provided herein. In practicing the methods,therapeutically effective amounts of the compounds or pharmaceuticalcompositions thereof are administered to a subject.

Methods of antagonizing receptors such as, for example, the 5-HT_(2B)receptor and/or D₂ and D₃ receptors with the compounds and compositionsdescribed herein are also provided herein. In practicing the methods,therapeutically effective amounts of the compounds or pharmaceuticalcompositions are administered.

Methods of agonizing receptors such as, for example, 5-HT_(1D) and5-HT_(1B), receptors with the compounds and pharmaceutical compositionsdescribed herein are also provided herein. In some embodiments, methodsof providing functional antagonist activity at, for example, the5-HT_(2B) receptor are provided. In practicing the methods,therapeutically effective amounts of the compounds or compositions areadministered.

DETAILED DESCRIPTION Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art to which this invention belongs. In the event that there is aplurality of definitions for a term herein, those in this sectionprevail unless stated otherwise.

“Alkyl” by itself or as part of another substituent, refers to asaturated or unsaturated, branched, straight-chain or cyclic monovalenthydrocarbon radical derived by the removal of one hydrogen atom from asingle carbon atom of a parent alkane, alkene or alkyne. Typical alkylgroups include, but are not limited to, methyl; ethyls such as ethanyl,ethenyl, ethynyl; propyls such as propan-1-yl, propan-2-yl,cyclopropan-1-yl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl(allyl), cycloprop-1-en-1-yl; cycloprop-2-en-1-yl, prop-1-yn-1-yl,prop-2-yn-1-yl, etc.; butyls such as butan-1-yl, butan-2-yl,2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl,but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl,but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like. Theterm “alkyl” is specifically intended to include groups having anydegree or level of saturation, i.e., groups having exclusively singlecarbon-carbon bonds, groups having one or more double carbon-carbonbonds, groups having one or more triple carbon-carbon bonds and groupshaving mixtures of single, double and triple carbon-carbon bonds. Wherea specific level of saturation is intended, the expressions “alkanyl,”“alkenyl,” and “alkynyl” are used. In some embodiments, an alkyl groupcomprises from 1 to 20 carbon atoms (C₁-C₂₀ alkyl). In otherembodiments, an alkyl group comprises from 1 to 10 carbon atoms (C₁-C₁₀alkyl). In still other embodiments, an alkyl group comprises from 1 to 6carbon atoms (C₁-C₆ alkyl).

“Alkanyl” by itself or as part of another substituent, refers to asaturated branched, straight-chain or cyclic alkyl radical derived bythe removal of one hydrogen atom from a single carbon atom of a parentalkane. Typical alkanyl groups include, but are not limited to,methanyl; ethanyl; propanyls such as propan-1-yl, propan-2-yl(isopropyl), cyclopropan-1-yl, etc.; butanyls such as butan-1-yl,butan-2-yl (sec-butyl), 2-methyl-propan-1-yl (isobutyl),2-methyl-propan-2-yl (t-butyl), cyclobutan-1-yl, etc.; and the like.

“Alkenyl” by itself or as part of another substituent, refers to anunsaturated branched, straight-chain or cyclic alkyl radical having atleast one carbon-carbon double bond derived by the removal of onehydrogen atom from a single carbon atom of a parent alkene. The groupmay be in either the cis or trans conformation about the double bond(s).Typical alkenyl groups include, but are not limited to, ethenyl;propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl(allyl), prop-2-en-2-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl;butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl,but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl,buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl,cyclobuta-1,3-dien-1-yl, etc.; and the like.

“Alkynyl” by itself or as part of another substituent refers to anunsaturated branched, straight-chain or cyclic alkyl radical having atleast one carbon-carbon triple bond derived by the removal of onehydrogen atom from a single carbon atom of a parent alkyne. Typicalalkynyl groups include, but are not limited to, ethynyl; propynyls suchas prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such as but-1-yn-1-yl,but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like.

“Acyl” by itself or as part of another substituent refers to a radical—C(O)R⁴⁰⁰, where R⁴⁰⁰ is hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl,substituted heteroalkyl, heteroarylalkyl or substituted heteroarylalkylas defined herein.

Representative examples include, but are not limited to formyl, acetyl,cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyland the like.

“Aryl” by itself or as part of another substituent, refers to amonovalent aromatic hydrocarbon group derived by the removal of onehydrogen atom from a single carbon atom of a parent aromatic ringsystem, as defined herein. Typical aryl groups include, but are notlimited to, groups derived from aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene,s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,rubicene, triphenylene, trinaphthalene and the like. In someembodiments, an aryl group comprises from 6 to 20 carbon atoms (C₆-C₂₀aryl). In other embodiments, an aryl group comprises from 6 to 15 carbonatoms (C₆-C₁₅ aryl). In still other embodiments, an aryl group comprisesfrom 6 to 15 carbon atoms (C₆-C₁₀ aryl).

“Arylalkyl” by itself or as part of another substituent, refers to anacyclic alkyl group in which one of the hydrogen atoms bonded to acarbon atom, typically a terminal or sp³ carbon atom, is replaced withan aryl group as, as defined herein. Typical arylalkyl groups include,but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl,naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethen-1-yl,naphthobenzyl, 2-naphthophenylethan-1-yl and the like. Where specificalkyl moieties are intended, the nomenclature arylalkanyl, arylalkenyland/or arylalkynyl is used. In some embodiments, an arylalkyl group is(C₆-C₃₀) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of thearylalkyl group is (C₁-C₁₀) alkyl and the aryl moiety is (C₆-C₂₀) aryl.In other embodiments, an arylalkyl group is (C₆-C₂₀) arylalkyl, e.g.,the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C₁-C₈)alkyl and the aryl moiety is (C₆-C₁₂) aryl. In still other embodiments,an arylalkyl group is (C₆-C₁₅) arylalkyl, e.g., the alkanyl, alkenyl oralkynyl moiety of the arylalkyl group is (C₁-C₅) alkyl and the arylmoiety is (C₆-C₁₀) aryl.

“Compounds” refers to compounds encompassed by structural formulaedisclosed herein and includes any specific compounds within theseformulae whose structure is disclosed herein. Compounds may beidentified either by their chemical structure and/or chemical name. Whenthe chemical structure and chemical name conflict, the chemicalstructure is determinative of the identity of the compound. Thecompounds described herein may contain one or more chiral centers and/ordouble bonds and therefore, may exist as stereoisomers, such asdouble-bond isomers (i.e., geometric isomers), enantiomers ordiastereomers. Accordingly, the chemical structures depicted hereinencompass all possible enantiomers and stereoisomers of the illustratedcompounds including the stereoisomerically pure form (e.g.,geometrically pure, enantiomerically pure or diastereomerically pure)and enantiomeric and stereoisomeric mixtures. Enantiomeric andstereoisomeric mixtures can be resolved into their component enantiomersor stereoisomers using separation techniques or chiral synthesistechniques well known to the skilled artisan. The compounds may alsoexist in several tautomeric forms including the enol form, the keto formand mixtures thereof. Accordingly, the chemical structures depictedherein encompass all possible tautomeric forms of the illustratedcompounds. The compounds described also include isotopically labeledcompounds where one or more atoms have an atomic mass different from theatomic mass conventionally found in nature. Examples of isotopes thatmay be incorporated into the compounds described herein include, but arenot limited to, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S, etc. In general,it should be understood that all isotopes of any of the elementscomprising the compounds described herein may be found in thesecompounds. Compounds may exist in unsolvated or unhydrated forms as wellas solvated forms, including hydrated forms and as N-oxides. In general,compounds may be hydrated, solvated or N-oxides. Certain compounds mayexist in multiple crystalline or amorphous forms. In general, allphysical forms are equivalent for the uses contemplated herein and areintended to be within the scope of the present invention. Further, itshould be understood, when partial structures of the compounds areillustrated, that brackets indicate the point of attachment of thepartial structure to the rest of the molecule.

“Heteroalkyl,” “Heteroalkanyl,” “Heteroalkenyl” and “Heteroalkynyl” bythemselves or as part of other substituents, refer to alkyl, alkanyl,alkenyl and alkynyl groups, respectively, in which one or more of thecarbon atoms (and optionally any associated hydrogen atoms), are each,independently of one another, replaced with the same or differentheteroatoms or heteroatomic groups. Typical heteroatoms or heteroatomicgroups which can replace the carbon atoms include, but are not limited

to, —O—, —S—, —N—, —Si—, —NH—, —S(O)—, —S(O)₂—, —S(O)NH—, —S(O)₂NH— andthe like and combinations thereof. The heteroatoms or heteroatomicgroups may be placed at any interior position of the alkyl, alkenyl oralkynyl groups. Typical heteroatomic groups which can be included inthese groups include, but are not limited to, —O—, —S—, —O—O—, —S—S—,—O—S—, —NR⁵⁰¹R⁵⁰²—,═N—N═, —N═N—, —N═N—NR⁵⁰³R⁵⁰⁴, —PR⁵⁰⁵—, —P(O)₂—, —POR⁵⁰⁶—, —O—P(O)₂—,—SO—, —SO₂—, —SnR⁵⁰⁷R⁵⁰⁸— and the like, where R⁵⁰¹, R⁵⁰², R⁵⁰³, R⁵⁰⁴,R⁵⁰⁵, R⁵⁰⁶, R⁵⁰⁷ and R⁵⁰⁸ are independently hydrogen, alkyl, substitutedalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substitutedcycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl.

“Heteroaryl” by itself or as part of another substituent, refers to amonovalent heteroaromatic radical derived by the removal of one hydrogenatom from a single atom of a parent heteroaromatic ring systems, asdefined herein. Typical heteroaryl groups include, but are not limitedto, groups derived from acridine, β-carboline, chromane, chromene,cinnoline, furan, imidazole, indazole, indole, indoline, indolizine,isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline,isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine,phenanthridine, phenanthroline, phenazine, phthalazine, pteridine,purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine,pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline,tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and thelike. In some embodiments, the heteroaryl group comprises from 5 to 20ring atoms (5-20 membered heteroaryl). In other embodiments, theheteroaryl group comprises from 5 to 10 ring atoms (5-10 memberedheteroaryl). Exemplary heteroaryl groups include those derived fromfuran, thiophene, pyrrole, benzothiophene, benzofuran, benzimidazole,indole, pyridine, pyrazole, quinoline, imidazole, oxazole, isoxazole andpyrazine.

“Heteroarylalkyl” by itself or as part of another substituent refers toan acyclic alkyl group in which one of the hydrogen atoms bonded to acarbon atom, typically a terminal or sp³ carbon atom, is replaced with aheteroaryl group. Where specific alkyl moieties are intended, thenomenclature heteroarylalkanyl, heteroarylakenyl and/orheteroarylalkynyl is used. In some embodiments, the heteroarylalkylgroup is a 6-21 membered heteroarylalkyl, e.g., the alkanyl, alkenyl oralkynyl moiety of the heteroarylalkyl is (C₁-C₆) alkyl and theheteroaryl moiety is a 5-15-membered heteroaryl. In other embodiments,the heteroarylalkyl is a 6-13 membered heteroarylalkyl, e.g., thealkanyl, alkenyl or alkynyl moiety is (C₁-C₃) alkyl and the heteroarylmoiety is a 5-10 membered heteroaryl.

“Hydrates” refers to incorporation of water into to the crystal latticeof a compound described herein, in stoichiometric proportions, resultingin the formation of an adduct. Methods of making hydrates include, butare not limited to, storage in an atmosphere containing water vapor,dosage forms that include water, or routine pharmaceutical processingsteps such as, for example, crystallization (i.e., from water or mixedaqueous solvents), lyophilization, wet granulation, aqueous filmcoating, or spray drying. Hydrates may also be formed, under certaincircumstances, from crystalline solvates upon exposure to water vapor,or upon suspension of the anhydrous material in water. Hydrates may alsocrystallize in more than one form resulting in hydrate polymorphism. Seee.g., (Guillory, K., Chapter 5, pp. 202-205 in Polymorphism inPharmaceutical Solids, (Brittain, H. ed.), Marcel Dekker, Inc., NewYork, N.Y., (1999)). The above methods for preparing hydrates are wellwithin the ambit of those of skill in the art, are completelyconventional and do not require any experimentation beyond what istypical in the art. Hydrates may be characterized and/or analyzed bymethods well known to those of skill in the art such as, for example,single crystal X-ray diffraction, X-ray powder diffraction, polarizingoptical microscopy, thermal microscopy, thermogravimetry, differentialthermal analysis, differential scanning calorimetry, IR spectroscopy,Raman spectroscopy and NMR spectroscopy. (Brittain, H., Chapter 6, pp.205-208 in Polymorphism in Pharmaceutical Solids, (Brittain, H. ed.),Marcel Dekker, Inc. New York, (1999)). In addition, many commercialcompanies routine offer services that include preparation and/orcharacterization of hydrates such as, for example, HOLODIAG, PharmaparcII, Voie de l'Innovation, 27 100 Val de Reuil, France(http://www.holodiag.com).

“Parent Aromatic Ring System” refers to an unsaturated cyclic orpolycyclic ring system having a conjugated π electron system.Specifically included within the definition of “parent aromatic ringsystem” are fused ring systems in which one or more of the rings arearomatic and one or more of the rings are saturated or unsaturated, suchas, for example, fluorene, indane, indene, phenalene, etc. Typicalparent aromatic ring systems include, but are not limited to,aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene,benzene, chrysene, coronene, fluoranthene, fluorene, hexacene,hexaphene, hexalene, as-indacene, s-indacene, indane, indene,naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene,pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene,picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene,trinaphthalene and the like.

“Preventing” or “prevention” refers to a reduction in risk of acquiringa disease or disorder (i.e., causing at least one of the clinicalsymptoms of the disease not to develop in a patient that may be exposedto or predisposed to the disease but does not yet experience or displaysymptoms of the disease). In some embodiments, “preventing” or“prevention” refers to reducing symptoms of the disease by taking thecompound in a preventative fashion. The application of a therapeutic forpreventing or prevention of a disease of disorder is known as‘prophylaxis.’ In some embodiments, the compounds provided hereinprovide superior prophylaxis because of lower long term side effectsover long time periods.

“Prodrug” refers to a derivative of a drug molecule that requires atransformation within the body to release the active drug. Prodrugs arefrequently (though not necessarily) pharmacologically inactive untilconverted to the parent drug.

“Promoiety” refers to a form of protecting group that when used to maska functional group within a drug molecule converts the drug into aprodrug. Typically, the promoiety will be attached to the drug viabond(s) that are cleaved by enzymatic or non-enzymatic means in vivo.

“Salt” refers to a salt of a compound, which possesses the desiredpharmacological activity of the parent compound. Such salts include: (1)acid addition salts, formed with inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like; or formed with organic acids such as acetic acid, propionicacid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvicacid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound isreplaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine and thelike. In some embodiments, the salt is pharmaceutically acceptable.

“Solvates” refers to incorporation of solvents into to the crystallattice of a compound described herein, in stoichiometric proportions,resulting in the formation of an adduct. Methods of making solvatesinclude, but are not limited to, storage in an atmosphere containing asolvent, dosage forms that include the solvent, or routinepharmaceutical processing steps such as, for example, crystallization(i.e., from solvent or mixed solvents) vapor diffusion, etc. Solvatesmay also be formed, under certain circumstances, from other crystallinesolvates or hydrates upon exposure to the solvent or upon suspensionmaterial in solvent. Solvates may crystallize in more than one formresulting in solvate polymorphism. See e.g., (Guillory, K., Chapter 5,pp. 205-208 in Polymorphism in Pharmaceutical Solids, (Brittain, H.ed.), Marcel Dekker, Inc., New York, N.Y., 1999)). The above methods forpreparing solvates are well within the ambit of those of skill in theart, are completely conventional do not require any experimentationbeyond what is typical in the art. Solvates may be characterized and/oranalyzed by methods well known to those of skill in the art such as, forexample, single crystal X-ray diffraction, X-ray powder diffraction,polarizing optical microscopy, thermal microscopy, thermogravimetry,differential thermal analysis, differential scanning calorimetry, IRspectroscopy, Raman spectroscopy and NMR spectroscopy. (Brittain, H.,Chapter 6, pp. 205-208 in Polymorphism in Pharmaceutical Solids,(Brittain, H. ed.), Marcel Dekker, Inc. New York, (1999)). In addition,many commercial companies routine offer services that includepreparation and/or characterization of solvates such as, for example,HOLODIAG, Pharmaparc II, Voie de l'Innovation, 27 100 Val de Reuil,France (http://www.holodiag.com).

“Substituted” when used to modify a specified group or radical, meansthat one or more hydrogen atoms of the specified group or radical areeach, independently of one another, replaced with the same or differentsubstituent(s). Substituent groups useful for substituting saturatedcarbon atoms in the specified group or radical include, but are notlimited to —R^(a), halo, —O⁻, ═O, —OR^(b), —SR^(b), —S⁻, —S,—NR^(c)R^(c), ═NR^(b), ═N—OR^(b), trihalomethyl, —CF₃, —CN, —OCN, —SCN,—NO, —NO₂, ═N₂, —N₃, —S(O)₂R^(b), —S(O)₂NR^(b), —S(O)₂O⁻, —S(O)₂OR^(b),—OS(O)₂R^(b), —OS(O)₂O⁻, —OS(O)₂OR^(b), —P(O)(O⁻)₂, —P(O)(OR^(b))(O⁻),—P(O)(OR^(b))(OR^(b)), —C(O)R^(b), —C(S)R^(b), —C(NR^(b))R^(b), —C(O)O⁻,—C(O)OR^(b), —C(S)OR^(b), —C(O)NR^(c)R^(c), —C(NR^(b))NR^(c)R^(c),—OC(O)R^(b), —OC(S)R^(b), —OC(O)O⁻, —OC(O)OR^(b), —OC(S)OR^(b),—NR^(b)C(O)R^(b), —NR^(b)C(S)R^(b), —NR^(b)C(O)O⁻, —NR^(b)C(O)OR^(b),—NR^(b)C(S)OR^(b), —NR^(b)C(O)NR^(c)R^(c), —NR^(b)C(NR^(b))R^(b) and—NR^(b)C(NR^(b))NR^(c)R^(c), where R^(a) is selected from the groupconsisting of alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, aryl,arylalkyl, heteroaryl and heteroarylalkyl; each R^(b) is independentlyhydrogen or R^(a); and each R^(c) is independently R^(b) oralternatively, the two R^(c)'s are taken together with the nitrogen atomto which they are bonded form a 4-, 5-, 6- or 7-memberedcycloheteroalkyl which may optionally include from 1 to 4 of the same ordifferent additional heteroatoms selected from the group consisting ofO, N and S. As specific examples, —NR^(c)R^(c) is meant to include —NH₂,—NH-alkyl, N-pyrrolidinyl and N-morpholinyl.

Similarly, substituent groups useful for substituting unsaturated carbonatoms in the specified group or radical include, but are not limited to,—R^(a), halo, —O⁻, —OR^(b), —SR^(b), —S⁻, —NR^(c)R^(c),

trihalomethyl, —CF₃, —CN, —OCN, —SCN, —NO, —NO₂, —N₃, —S(O)₂R^(b),—S(O)₂O⁻, —S(O)₂OR^(b), —OS(O)₂R^(b), —OS(O)₂O⁻, —OS(O)₂OR^(b),—P(O)(O⁻)₂, —P(O)(OR^(b))(O⁻), —P(O) (OR^(b))(OR^(b)), —C(O)R^(b),—C(S)R^(b), —C(NR^(b))R^(b), —C(O)O⁻, —C(O)OR^(b), —C(S)OR^(b), —C(O)NR^(c)R^(c), —C(NR^(b))NR^(c)R^(c), —OC(O)R^(b), —OC(S)R^(b), —OC(O)O⁻,—OC(O)OR^(b), —OC(S)OR^(b), —NR^(b)C(O)R^(b), —NR^(b)C(S)R^(b),—NR^(b)C(O)O⁻, —NR^(b)C(O)OR^(b), —NR^(b)C(S)OR^(b), —NR^(b)C(O)NR^(c)R^(c), —NR^(b)C(NR^(b))R^(b) and —NR^(b)C(NR^(b))NR^(c)R^(c),where R^(a), R^(b) and R^(c) are as previously defined.

Substituent groups useful for substituting nitrogen atoms in heteroalkyland cycloheteroalkyl groups include, but are not limited

to, —R^(a), —O⁻, —OR^(b), —SR^(b), —S⁻, —NR^(c)R^(c),

trihalomethyl, —CF₃, —CN, —NO, —NO₂, —S(O)₂R^(b), —S(O)₂O⁻,—S(O)₂OR^(b), —OS(O)₂R^(b), —OS(O)₂O⁻, —OS(O)₂OR^(b), —P(O)(O⁻)₂,—P(O)(OR^(b))(O⁻), —P(O)(OR^(b))(OR^(b)), —C(O) R^(b), —C(S)R^(b),—C(NR^(b))R^(b), —C(O)OR^(b), —C(S)OR^(b), —C(O)NR^(c)R^(c),—C(NR^(b))NR^(c)R^(c), —OC(O)R^(b), —OC(S)R^(b), —OC(O)OR^(b),—OC(S)OR^(b), —NR^(b)C(O)R^(b), —NR^(b)C(S)R^(b), —NR^(b)C(O) OR^(b),—NR^(b)C(S)OR^(b), —NR^(b)C(O)NR^(c)R^(c), —NR^(b)C(NR^(b))R^(b) and—NR^(b)C(NR^(b))NR^(c)R^(c), where R^(a), R^(b) and R^(c) are aspreviously defined.

Substituent groups from the above lists useful for substituting otherspecified groups or atoms will be apparent to those of skill in the art.The substituents used to substitute a specified group can be furthersubstituted, typically with one or more of the same or different groupsselected from the various groups specified above. In some embodiments,substituents are limited to the groups above.

“Subject,” “individual” or “patient” is used interchangeably herein andrefers to a vertebrate, preferably a mammal. Mammals include, but arenot limited to, murines, rodents, simians, humans, farm animals, sportanimals and pets.

“Treating” or “treatment” of any disease or disorder refers, in someembodiments, to ameliorating the disease or disorder (i.e., arresting orreducing the development of the disease or at least one of the clinicalsymptoms thereof). Treatment may also be considered to includepreemptive or prophylactic administration to ameliorate, arrest orprevent the development of the disease or at least one of the clinicalsymptoms. Treatment can also refer to the lessening of the severityand/or the duration of one or more symptoms of a disease or disorder. Ina further feature, the treatment rendered has lower potential for longterm side effects over multiple years. In other embodiments “treating”or “treatment” refers to ameliorating at least one physical parameter,which may not be discernible by the patient. In yet other embodiments,“treating” or “treatment” refers to inhibiting the disease or disorder,either physically, (e.g., stabilization of a discernible symptom),physiologically, (e.g., stabilization of a physical parameter) or both.In yet other embodiments, “treating” or “treatment” refers to delayingthe onset of the disease or disorder.

“Therapeutically effective amount” means the amount of a compound that,when administered to a patient for treating a disease, is sufficient toeffect such treatment for the disease. The “therapeutically effectiveamount” will vary depending on the compound, the disease and itsseverity and the age, weight, adsorption, distribution, metabolism andexcretion etc., of the patient to be treated.

“Vehicle” refers to a diluent, excipient or carrier with which acompound is administered to a subject. In some embodiments, the vehicleis pharmaceutically acceptable.

Compounds

In some aspects, a compound of structural Formula (I) is provided:

or polymorphs, salts, hydrates or solvates thereof, wherein: R₁ ishydrogen, alkyl, substituted alkyl, heteroalkyl, substitutedheteroalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,halo, haloalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,substituted heteroarylalkyl, —S(O)_(j)R₁₀₁, —C(O)NR₁₀₂R₁₀₃ or —CO₂R₁₀₄;R₂ is alkyl, substituted alkyl, acyl, substituted acyl, halo, haloalkyl,heteroalkyl, substituted heteroalkyl, arylalkyl, substituted arylalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl, substitutedheteroarylalkyl, —NO₂, —N₃, —S(O)_(k)R₁₁₀, —OR₁₁₁, —NR₁₁₂R₁₁₃,—C(O)NR₁₁₄R₁₁₅, —OC(O)NR₁₁₆R₁₁₇, —CO₂R₁₁₈ or —OC(O)R₁₁₉; n is 0, 1, 2 or3; R₃ is hydrogen, alkyl, substituted alkyl, haloalkyl, heteroalkyl,substituted heteroalkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl orsubstituted heteroarylalkyl; R₄ and R₅ are independently hydrogen,alkyl, substituted alkyl, halo,haloalkyl, —OR₁₂₀, —OC(O)NR₁₂₁R₁₂₂, —OC(O)R₁₂₃ or together with theatoms to which they are attached form a double bond; R₆ and R₇ areindependently hydrogen, acyl, subsisted acyl, alkyl, substituted alkyl,haloalkyl, heteroalkyl or substituted heteroalkyl; X is —S—, —SO₂— or—NR₈—; Z is —CH₂— or —NR₉—; a is 0 or 1; R₈, R₉, R₁₀₂-R₁₀₄ and R₁₁₁-R₁₂₃are independently hydrogen, alkyl, substituted alkyl, acyl, substitutedacyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,haloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl or substituted heteroarylalkyl; R₁₀₁ andR₁₁₀ are independently alkyl, substituted alkyl, acyl, substituted acyl,aryl, substituted aryl, arylalkyl, substituted arylalkyl, halo,haloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl or substituted heteroarylalkyl; andoptionally, R₁ and R₈ along with the atoms to which they are attachedform a 5, 6 or 7 membered ring.In some embodiments R₆ and R₇ are not acyl.

In some embodiments, when one of R₆ and R₇ is hydrogen or alkyl theother of R₆ and R₇ is not hydrogen or alkyl.

In some embodiments, R₁-R₉, R₁₀₂-R₁₀₄ and R₁₁₁-R₁₂₃ are independentlyalkyl, heteroalkyl substituted with one or more fluorine atoms or alkylsubstituted with one or more fluorine atoms. In other embodiments, R₁,R₃ and R₈ are independently alkyl, alkyl substituted with one or morefluorine atoms, heteroalkyl substituted with one or more fluorine atoms,arylalkyl substituted with one or more fluorine atoms or heteroarylalkylsubstituted with one or more fluorine atoms.

In some embodiments, R₁ and R₈ are independently alkyl, alkylsubstituted with one or more fluorine atoms, heteroalkyl substitutedwith one or more fluorine atoms, arylalkyl substituted with one or morefluorine atoms or heteroarylalkyl substituted with one or more fluorineatoms. In other embodiments, R₁ is hydrogen, alkyl, substituted alkyl,haloalkyl, heteroalkyl or substituted heteroalkyl. In still otherembodiments, R₁ is hydrogen, alkyl or substituted alkyl. In still otherembodiments, R₁ is hydrogen, alkyl or alkyl substituted with one or morefluorine atoms.

In some embodiments, R₂ is alkyl, substituted alkyl, haloalkyl, acyl,substituted acyl, halo, —OR₁₁₁, —NR₁₁₂R₁₁₃, —C(O)NR₁₁₄R₁₁₅, —CO₂R₁₁₈ or—OC(O)R₁₁₉. In other embodiments, R₂ is alkyl, substituted alkyl,haloalkyl, acyl, halo, —OR₁₁₁, —C(O)NR₁₁₄R₁₁₅ or —CO₂R₁₁₈.

In some embodiments, n is 0 or 1. In other embodiments, n is 0.

In some embodiments, R₃ is hydrogen, alkyl, substituted alkyl,haloalkyl, heteroalkyl or substituted heteroalkyl. In other embodiments,R₃ is hydrogen, alkyl or alkyl substituted with one or more fluorineatoms.

In some embodiments, R₄ and R₅ are independently hydrogen, alkyl,substituted alkyl, haloalkyl, —OR₁₂₀ or together with the atoms to whichthey are attached form a double bond. In other embodiments, R₄ and R₅are independently hydrogen, —OR₁₂₀ or together with the atoms to whichthey are attached form a double bond. In still other embodiments, R₄ andR₅ together with the atoms to which they are attached form a doublebond.

In some embodiments, R₆ and R₇ are independently, hydrogen, alkyl,substituted alkyl, acyl or substituted acyl. In other embodiments, R₆and R₇ are independently, hydrogen, acyl or substituted acyl. In stillother embodiments, R₆ and R₇ are independently, hydrogen, alkyl,substituted alkyl or substituted acyl. In still other embodiments, R₆and R₇ are independently, hydrogen, or substituted acyl.

In some embodiments, R₈, R₉, R₁₀₂-R₁₀₄ and R₁₁₁-R₁₂₃ are independentlyhydrogen, alkyl, substituted alkyl, arylalkyl or substituted arylalkyl.In other embodiments, R₈, R₉, R₁₀₂-R₁₀₄ and R₁₁₁-R₁₂₃ are independentlyhydrogen, alkyl or arylalkyl. In still other embodiments, R₈, R₉,R₁₀₂-R₁₀₄ and R₁₁₁-R₁₂₃ are hydrogen.

In some embodiments, R₈ is hydrogen, alkyl, substituted alkyl, arylalkylor substituted arylalkyl. In other embodiments, R₈ is hydrogen, alkyl,alkyl substituted with one or more fluorine atoms, arylalkyl orarylalkyl alkyl substituted with one or more fluorine atoms. In stillother embodiments, R₈ is hydrogen, alkyl or arylalkyl. In still otherembodiments, R₈ is hydrogen, alkyl substituted with one or more fluorineatoms or arylalkyl substituted with one or more fluorine atoms. In stillother embodiments, R₈ is hydrogen.

In some embodiments, R₁₀₁ and R₁₁₀ are independently alkyl, substitutedalkyl, arylalkyl or substituted arylalkyl. In other embodiments, R₁₀₁and R₁₁₀ are independently alkyl or arylalkyl.

In some embodiments, a compound of structural formula (II) is provided:

wherein R₇ is

R₁₀ is alkyl, substituted alkyl, haloalkyl, heteroalkyl, or substitutedheteroalkyl; Y is —S(O)_(k)R₁₁, —OR₁₂ or —NR₁₃R₁₄; k is 0, 1 or 2; b is1, 2, 3 or 4; R₁₁ is alkyl, substituted alkyl, acyl, substituted acyl,aryl, substituted aryl, arylalkyl, substituted arylalkyl, halo,haloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl or substituted heteroarylalkyl; and R₁₂-R₁₄are independently hydrogen, alkyl, substituted alkyl, acyl, substitutedacyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,haloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl or substituted heteroarylalkyl. In someembodiments, b is 1 or 2. In other embodiments, b is 1. In still otherembodiments, Y is —OR₁₂ or —NR₁₃R₁₄. In still other embodiments, Y is—OR₁₂. In still other embodiments, R₈, R₉, R₁₀₂-R₁₀₄ and R₁₁₁-R₁₂₃ areindependently hydrogen, alkyl, substituted alkyl, arylalkyl orsubstituted arylalkyl. In still other embodiments, R₈, R₉, R₁₂-R₁₄,R₁₀₂-R₁₀₄ and R₁₁₁-R₁₂₃ are independently hydrogen, alkyl or arylalkyl.In still other embodiments, R₈, R₉, R₁₂-R₁₄, R₁₀₂-R₁₀₄ and R₁₁₁-R₁₂₃ arehydrogen. In still other embodiments, R₈, R₉, and R₁₂-R₁₄ areindependently hydrogen, alkyl, substituted alkyl, arylalkyl orsubstituted arylalkyl. In still other embodiments, R₈, R₉, and R₁₂-R₁₄are independently hydrogen, alkyl or arylalkyl. In still otherembodiments, R₈, R₉, and R₁₂-R₁₄ are hydrogen. In still otherembodiments, R₁, R₃ and R₈ are independently alkyl, alkyl substitutedwith one or more fluorine atoms, heteroalkyl substituted with one ormore fluorine atoms, arylalkyl substituted with one or more fluorineatoms or heteroarylalkyl substituted with one or more fluorine atoms. Instill other embodiments, R₁ and R₈ are independently alkyl, alkylsubstituted with one or more fluorine atoms, heteroalkyl substitutedwith one or more fluorine atoms, arylalkyl substituted with one or morefluorine atoms or heteroarylalkyl substituted with one or more fluorineatoms. In still other embodiments, R₈ is hydrogen, alkyl, alkylsubstituted with one or more fluorine atoms, arylalkyl or arylalkylalkyl substituted with one or more fluorine atoms. In still otherembodiments, R₈ is hydrogen, alkyl or arylalkyl. In still otherembodiments, R₈ is hydrogen, alkyl substituted with one or more fluorineatoms or arylalkyl substituted with one or more fluorine atoms. In stillother embodiments, R₈ is hydrogen. In still other embodiments, R₁₁, R₁₀₁and R₁₁₀ are independently alkyl, substituted alkyl, arylalkyl orsubstituted arylalkyl. In still other embodiments, R₁₁, R₁₀₁ and R₁₁₀are independently alkyl or arylalkyl.

In some embodiments, R₁ is hydrogen, alkyl, substituted alkyl,heteroalkyl or substituted heteroalkyl; R₂ is alkyl, substituted alkyl,acyl, halo, —OR₁₁₁, —C(O)NR₁₁₄R₁₁₅ or —CO₂R₁₁₈; n is 0 or 1; R₃ ishydrogen, alkyl, substituted alkyl, heteroalkyl or substitutedheteroalkyl; R₄ and R₅ are independently hydrogen, alkyl, substitutedalkyl, —OR₁₂₀ or together with the atoms to which they are attached forma double bond; R₁₀ is alkyl or substituted alkyl; b is 1 or 2; Y is—OR₁₂ or —NR₁₃R₁₄; R₈, R₉, R₁₂-R₁₄, R₁₀₂-R₁₀₄ and R₁₁₁-R₁₂₃ areindependently hydrogen, alkyl, substituted alkyl, arylalkyl orsubstituted arylalkyl; and R₁₀₁ and R₁₁₀ are independently alkyl,substituted alkyl, arylalkyl or substituted arylalkyl. In otherembodiments, R₁, R₃ and R₈ are independently alkyl, alkyl substitutedwith one or more fluorine atoms, heteroalkyl substituted with one ormore fluorine atoms, arylalkyl substituted with one or more fluorineatoms or heteroarylalkyl substituted with one or more fluorine atoms. Instill other embodiments, R₁ and R₈ are independently alkyl, alkylsubstituted with one or more fluorine atoms, heteroalkyl substitutedwith one or more fluorine atoms, arylalkyl substituted with one or morefluorine atoms or heteroarylalkyl substituted with one or more fluorineatoms. R₈ is hydrogen, alkyl, alkyl substituted with one or morefluorine atoms, arylalkyl or arylalkyl alkyl substituted with one ormore fluorine atoms.

In some embodiments, R₁ is hydrogen, alkyl, substituted alkyl,heteroalkyl or substituted heteroalkyl; R₂ is alkyl, substituted alkyl,acyl, halo, —OR₁₁₁, —C(O)NR₁₁₄R₁₁₅ or —CO₂R₁₁₈; n is 0 or 1; R₃ ishydrogen, alkyl, substituted alkyl, heteroalkyl or substitutedheteroalkyl; R₄ and R₅ are independently hydrogen, alkyl, substitutedalkyl, —OR₁₂₀ or together with the atoms to which they are attached forma double bond; R₁₀ is alkyl or substituted alkyl; b is 1 or 2; Y is—OR₁₂ or —NR₁₃R₁₄; R₈, R₁₂-R₁₄, R₁₀₂-R₁₀₄ and R₁₁₁-R₁₂₃ areindependently hydrogen, alkyl or arylalkyl; and R₁₀₁ and R₁₁₀ areindependently alkyl or arylalkyl. In other embodiments, R₁, R₃ and R₈are independently alkyl, alkyl substituted with one or more fluorineatoms, heteroalkyl substituted with one or more fluorine atoms,arylalkyl substituted with one or more fluorine atoms or heteroarylalkylsubstituted with one or more fluorine atoms. In still other embodiments,R₁ and R₈ are independently alkyl, alkyl substituted with one or morefluorine atoms, heteroalkyl substituted with one or more fluorine atoms,arylalkyl substituted with one or more fluorine atoms or heteroarylalkylsubstituted with one or more fluorine atoms. In still other embodiments,R₈ is hydrogen, alkyl, alkyl substituted with one or more fluorineatoms, arylalkyl or arylalkyl alkyl substituted with one or morefluorine atoms.

In some embodiments, R₁ is hydrogen, alkyl, substituted alkyl,heteroalkyl or substituted heteroalkyl; R₂ is alkyl, substituted alkyl,acyl, halo, —OR₁₁₁, —C(O)NR₁₁₄R₁₁₅ or —CO₂R₁₁₈; n is 0 or 1; R₃ ishydrogen, alkyl, substituted alkyl, heteroalkyl or substitutedheteroalkyl; R₄ and R₅ are independently hydrogen, alkyl, substitutedalkyl, —OR₁₂₀ or together with the atoms to which they are attached forma double bond; R₁₀ is alkyl or substituted alkyl; b is 1 or 2; Y is—OR₁₂ or —NR₁₃R₁₄; R₈, R₉, R₁₂-R₁₄, R₁₀₂-R₁₀₄ and R₁₁₁-R₁₂₃ areindependently hydrogen, alkyl or arylalkyl; and R₁₀₁ and R₁₁₀ areindependently alkyl or arylalkyl. In other embodiments, R₁, R₃ and R₈are independently alkyl, alkyl substituted with one or more fluorineatoms, heteroalkyl substituted with one or more fluorine atoms,arylalkyl substituted with one or more fluorine atoms or heteroarylalkylsubstituted with one or more fluorine atoms. In still other embodiments,R₁ and R₈ are independently alkyl, alkyl substituted with one or morefluorine atoms, heteroalkyl substituted with one or more fluorine atoms,arylalkyl substituted with one or more fluorine atoms or heteroarylalkylsubstituted with one or more fluorine atoms. In still other embodiments,R₈ is hydrogen, alkyl, alkyl substituted with one or more fluorineatoms, arylalkyl or arylalkyl alkyl substituted with one or morefluorine atoms.

In some embodiments, R₁ is hydrogen, alkyl or substituted alkyl, R₂ isalkyl, substituted alkyl, acyl, halo, —OR₁₁₁, —C(O)NR₁₁₄R₁₁₅ or—CO₂R₁₁₈; R₃ is hydrogen, alkyl or alkyl substituted with one or morefluorine atoms; R₄ and R₅ are independently hydrogen, —OR₁₂₀ or togetherwith the atoms to which they are attached form a double bond; R₁₀ isalkyl or alkyl substituted with one or more fluorine atoms; b is 1; Y is—OR₁₂ or —NR₁₃R₁₄; R₈, R₉, R₁₂-R₁₄, R₁₀₂-R₁₀₄, R₁₁₁-R₁₂₃ areindependently hydrogen, alkyl, substituted alkyl, arylalkyl orsubstituted arylalkyl; and R₁₀₁ and R₁₁₀ are independently alkyl,substituted alkyl, arylalkyl or substituted arylalkyl.

In some embodiments, R₁ is hydrogen, alkyl or substituted alkyl; R₂ isalkyl, substituted alkyl, acyl, halo, —OR₁₁₁, —C(O)NR₁₁₄R₁₁₅ or—CO₂R₁₁₈; R₃ is hydrogen or alkyl; R₄ and R₅ are independently hydrogen,—OR₁₂₀ or together with the atoms to which they are attached form adouble bond; R₆ is hydrogen; R₇ is alkyl or alkyl substituted with oneor more fluorine atoms; b is 1; Y is —OR₁₂ or —NR₁₃R₁₄; R₈, R₈, R₁₂-R₁₄,R₁₀₂-R₁₀₄ and R₁₁₁-R₁₂₃ are independently hydrogen, alkyl, substitutedalkyl, arylalkyl or substituted arylalkyl; and R₁₀₁ and R₁₁₀ areindependently alkyl, substituted alkyl, arylalkyl or substitutedarylalkyl.

In some embodiments, R₁ is hydrogen, alkyl or substituted alkyl; R₂ isalkyl, substituted alkyl, acyl, halo, —OR₁₁₁, —C(O)NR₁₁₄R₁₁₅ or—CO₂R₁₁₈; R₃ is hydrogen or alkyl; R₄ and R₅ are independently hydrogen,—OR₁₂₀ or together with the atoms to which they are attached form adouble bond; R₁₀ is alkyl or alkyl substituted with one or more fluorineatoms; b is 1; Y is —OR₁₂; R₈, R₉, R₁₃, R₁₀₂-R₁₀₄ and R₁₁₁-R₁₂₃ arehydrogen, alkyl or arylalkyl; and R₁₀₁ and R₁₁₀ are independently alkylor arylalkyl.

In some of the above embodiments, n is 0.

In some embodiments, R₁ is halo, hydrogen, alkyl or substituted alkyl;R₃ is alkyl or alkyl substituted with one or more fluorine atoms; R₁₀ isalkyl or substituted alkyl; and Y is —OR₁₂. In other embodiments, X is—NR₈ and R₈ is hydrogen, alkyl or substituted alkyl. In still otherembodiments, R₄ and R₅ are independently hydrogen, alkyl —OR₁₂₀ ortogether with the atoms to which they are attached form a double bond.In still other embodiments, R₁ is halo, hydrogen or substituted alkyl, Xis —NR₈, R₈ is hydrogen, alkyl or substituted alkyl and R₄ and R₅ areindependently hydrogen, —OR₁₂₀ or together with the atoms to which theyare attached form a double bond. In still other embodiments, R₁ ishydrogen; X is —NR₈, R₈ is hydrogen, and R₄ and R₈ are hydrogen, —OR₁₂₀or together with the atoms to which they are attached form a doublebond. In still other embodiments, R₁ is hydrogen; X is —NR₈, R₈ ishydrogen, and R₄ and R₅ are hydrogen or —OR₁₂₀. In still otherembodiments, R₁ is hydrogen; X is —NR₈, R₈ is hydrogen, and R₄ and R₅are hydrogen or —OR₁₂₀, R₁₂₀ is methyl or hydrogen and Y is OH.

In some embodiments, X is —NR₈— and R₈ is hydrogen or substituted alkyl.In other embodiments, X is —NR₈—, R₈ is hydrogen or substituted alkyland Z is —OH. In still other embodiments, X is —NR₈—, R₈ is hydrogen orsubstituted alkyl, R₄ and R₅ form a double bond or are hydrogen and Y is—OH. In still other embodiments, X is —NR₈—, R₈ is hydrogen or —CF₃, R₁is hydrogen, —CF₃ or Br, R₃ is methyl, R₄ and R₅ form a double bond orare hydrogen, R₇ is —CF₃, —CH₂CF₃, —C₂H₅ or —C₂F₅ and Y is —OH. In stillother embodiments, X is —NH—, R₁ is hydrogen, R₃ is methyl, R₄ and R₅form a double bond or are hydrogen, R₇ is —CF₃, —CH₂CF₃ or —C₂F₅ and Yis —OH. In still other embodiments, X is —NCF₃—, R₁ is hydrogen, R₃ ismethyl, R₄ and R₅ form a double bond or are hydrogen, R₇ is —CF₃,—CH₂CF₃ or —C₂F₅ and Y is —OH. In still other embodiments, X is —NH—, R₁is —CF₃, R₃ is methyl, R₄ and R₅ form a double bond or are hydrogen, R₇is —CF₃, —CH₂CF₃, or —C₂F₅ and Y is —OH. In still other embodiments, Xis —NH—, R₁ is —Br, R₃ is methyl, R₄ and R₅ form a double bond or arehydrogen, R₇ is —CF₃, —CH₂CF₃, or —C₂F₅ and Y is —OH.

In some embodiments, a compound of structural formula (III) is provided:

wherein R₇ is

R₁₀ is methyl, b is 1 and Y is OH.

In some embodiments, a compound of structural formula (IV) is provided:

where R₁ is halo, hydrogen, alkyl or substituted alkyl; R₃ is alkyl; R₁₀is alkyl or substituted alkyl; and Y is —OR₁₂. In some embodiments, X is—S— or —SO₂— and R₁ is hydrogen. In other embodiments, X is —S— or—SO₂—, R₁ is hydrogen, R₇ is alkyl and Z is —OH. In still otherembodiments, X is —S— or —SO₂—, R₁ is hydrogen, R₄ and R₅ are a doublebond, R₇ is alkyl and Z is —OH.

In some embodiments, a compound of structural formula (V) is provided:

wherein R₇ is

R₁₀ is methyl, b is 1 and Y is OH.

In some embodiments, a compound of structural formula (VI) is provided:

where wherein R₇ is

R₁₀ is methyl, b is 1 and Y is OH.

In some of the above embodiments, when a is 1, Z is —NR₉ and X is —NR₈,R₁ is not hydrogen, (C₁-C₃) alkyl or (C₁-C₃) alkyl substituted with oneor more fluorine atoms; when a is 0, X is —NR₈, R₁ is hydrogen orhalogen and one of R₆ or R₇ is hydrogen the other of R₆ or R₇ is notsubstituted alkyl or substituted arylalkyl; and when a is 0, X is —NR₈,R₁ is hydrogen, (C₁-C₄) alkyl, substituted (C₁-C₄) alkyl, (C₁-C₄) alkylsubstituted with one or more fluorine atoms, (C₁-C₄) acyl, substituted(C₁-C₄) acyl, (C₁-C₄) heteroalkyl or substituted (C₁-C₄) heteroalkyl, R₂is hydrogen, (C₁-C₄) alkyl, substituted (C₁-C₄) alkyl, (C₁-C₄) alkylsubstituted with one or more fluorine atoms, (C₁-C₄) acyl, substituted(C₁-C₄) acyl, halogen, —OH, (C₁-C₄) heteroalkyl or substituted (C₁-C₄)heteroalkyl, and one of R₆ or R₇ is hydrogen, (C₁-C₄) alkyl, substituted(C₁-C₄) alkyl, (C₁-C₄) alkyl substituted with one or more fluorineatoms, (C₁-C₄) acyl, substituted (C₁-C₄) acyl, halogen, —OH, (C₁-C₄)heteroalkyl or substituted (C₁-C₄) heteroalkyl, the other of R₆ or R₇ isnot substituted alkyl. In other of the above embodiments, when a is 0, Xis —NR₈, and one of R₆ or R₇ is hydrogen, the other is not hydrogen oralkyl. In still other of the above embodiments, when a is 0, X is —NR₈,and one of R₆ or R₇ is alkyl, the other is not hydrogen or alkyl. Instill other of the above embodiments, when a is 1, Z is —NR₉ and X is—NR₈ that R₁ is not hydrogen, (C₁-C₃) alkyl or (C₁-C₃) alkyl substitutedwith one or more fluorine atoms. In still other of the aboveembodiments, when a is 0, X is —NR₈, R₁ is hydrogen or halogen and oneof R₆ or R₇ is hydrogen the other of R₆ or R₇ is not substituted alkylor substituted arylalkyl. In still other of the above embodiments, whena is 0, X is —NR₈, R₁ is hydrogen, (C₁-C₄) alkyl, substituted (C₁-C₄)alkyl, (C₁-C₄) alkyl substituted with one or more fluorine atoms,(C₁-C₄) acyl, substituted (C₁-C₄) acyl, (C₁-C₄) heteroalkyl orsubstituted (C₁-C₄) heteroalkyl, R₂ is hydrogen, (C₁-C₄) alkyl,substituted (C₁-C₄) alkyl, (C₁-C₄) alkyl substituted with one or morefluorine atoms, (C₁-C₄) acyl, substituted (C₁-C₄) acyl, halogen, —OH,(C₁-C₄) heteroalkyl or substituted (C₁-C₄) heteroalkyl, and one of R₆ orR₇ is hydrogen, (C₁-C₄) alkyl, substituted (C₁-C₄) alkyl, (C₁-C₄) alkylsubstituted with one or more fluorine atoms, (C₁-C₄) acyl, substituted(C₁-C₄) acyl, halogen, —OH, (C₁-C₄) heteroalkyl or substituted (C₁-C₄)heteroalkyl, the other of R₆ or R₇ is not substituted alkyl.

In some embodiments, X is —NR₈—, R₁ is hydrogen, alkyl or substitutedalkyl, R₃ is alkyl, a is 0, n is 0, R₆ is H, R₇ is substituted alkyl andR₈ is hydrogen, alkyl or substituted alkyl. In other embodiments, X is—NR₈—, R₁ is hydrogen, alkyl or alkyl substituted with one or morefluorine atoms, R₃ is alkyl, R₇ is substituted alkyl and R₈ is hydrogen,alkyl or alkyl substituted with one or more fluorine atoms. In stillother embodiments, X is —NR₈—, R₁ is hydrogen, alkyl or alkylsubstituted with one or more fluorine atoms, R₃ is methyl, R₇ is—CH(C₂H₅)CH₂OH, and R₈ is hydrogen, alkyl or alkyl substituted with oneor more fluorine atoms. In still other embodiments, X is —NR₈—, R₁ ishydrogen, alkyl or alkyl substituted with one or more fluorine atoms, R₃is methyl, R₇ is —CH(CF₂R₄₀)CH₂OH, R₈ is hydrogen, alkyl or alkylsubstituted with one or more fluorine atoms and R₄₀ is alkyl. In stillother embodiments, X is —NR₈—, R₁ is hydrogen, alkyl or alkylsubstituted with one or more fluorine atoms, R₃ is methyl, R₇ is—CH(CHFR₄₀)CH₂OH, R₈ is hydrogen, alkyl or alkyl substituted with one ormore fluorine atoms and R₄₀ is alkyl.

In some embodiments, a compound of structural Formula (VII) is provided:

wherein R₁ is C₃-C₆ cycloalkyl or substituted C₃-C₆ cycloalkyl; R₃ ishydrogen or alkyl; R₄ and R₅ are independently hydrogen,halo, —OR₁₂₀, —OC(O)NR₁₂₁R₁₂₂, —OC(O)R₁₂₃ or together with the atoms towhich they are attached form a double bond; R₆ and R₇ are independentlyhydrogen or alkyl, R₈ and R₉, are independently hydrogen or alkyl; R₁₂₀is hydrogen, methyl or alkyl; R₁₂₁, R₁₂₂ are independently hydrogen oralkyl; and R₁₂₃ is alkyl; provided that R₁ is cyclopropyl or substitutedcyclopropyl only when R₄ and R₅ are both hydrogen or form a double bond.In some embodiments, R₄ and R₅ are independently hydrogen, halo or—OR₁₂₀. In some embodiments, R₆ and R₇ are alkyl. In some embodiments,R₆ and R₇ are identical alkyl groups. In some embodiments, R₁ iscyclopropyl; R₃ is methyl; R₄ and R₅ are hydrogen; R₆ and R₇ are ethyl,R₈ and R₉, are hydrogen.

In some embodiments, a compound of structural Formula (VIII) isprovided:

wherein R₁ is hydrogen, alkyl or halo; R₃ is hydrogen, alkyl; R₄ and R₅are independently hydrogen, halo, —OR₁₂₀, —OC(O)NR₁₂₁R₁₂₂, —OC(O)R₁₂₃ ortogether with the atoms to which they are attached form a double bond;R₆ and R₇ are independently hydrogen, alkyl or substituted alkyl; R₈ andR₉, are independently hydrogen or alkyl; R₁₂₀ is hydrogen, methyl oralkyl; R₁₂₁, R₁₂₂ are independently hydrogen or alkyl; and R₁₂₃ isalkyl; and optionally, R₁ and R₈ along with the atoms to which they areattached form a 5, 6 or 7 membered ring.

In some embodiments, a compound of structural Formula (IX) is provided:

wherein R₁ is hydrogen, alkyl or halo; R₃ is hydrogen, alkyl; R₄ and R₅are independently hydrogen, halo, —OR₁₂₀, —OC(O)NR₁₂₁R₁₂₂, —OC(O)R₁₂₃ ortogether with the atoms to which they are attached form a double bond;R₈ is hydrogen or alkyl; R₁₂ is hydrogen, alkyl or —C(O)R₁₃; R₁₃ isalkyl; R₁₂₀ is hydrogen, methyl or alkyl; R₁₂₁, R₁₂₂ are independentlyhydrogen or alkyl; and R₁₂₃ is alkyl; and optionally, R₁ and R₈ alongwith the atoms to which they are attached form a 5, 6 or 7 memberedring. In some embodiments, R₁₂ is hydrogen only when R₄ is —OCH₃ or —OH.In other embodiments, R₂ is hydrogen or methyl. In still otherembodiments, R₂ is hydrogen, cyclopropyl or bromo. In still otherembodiments, R₄ is —OH or —OMe and R₅ is hydrogen.

In some embodiments, compounds of the structure below are provided:

The structures with dotted line represent two compounds, one with asingle bond and one with a double bond, respectively.

Metabolites of compounds of Formula (I) may be pharmaceutically active.Accordingly, in some embodiments, metabolites of the compounds ofFormula (I) have similar pharmaceutically activity as the compounds ofFormula (I). In other embodiments, metabolites of the compounds ofFormula (I) have minimal pharmaceutical activity when compared tocompounds of Formula (I). In still other embodiments, the metabolites ofthe compound of Formula (I) are not 5HT_(2b) agonists. In still otherembodiments, the compounds of Formula (I) are not 5HT_(2b) agonists andthe metabolites of the compound of Formula (I) are not 5HT_(2b)agonists.

Exemplary methods for the preparation of compounds of Formula (I) and(II) for use in the compositions and methods provided herein aredescribed below but other methods known in the art can be used toprepare the ergoline derivatives disclosed herein.

In some embodiments, compounds of Formula (I) can be prepared byfunctionalization of compounds of Formula (IX) which are readilyavailable by hydrolysis of readily available alkaloids. Many methodsexist for conversion of acids (IX) to compounds of Formulas (I),respectively. Accordingly, preparation of compounds of Formula (I) fromacids of Formula (IX) is well within the ambit of the skilled artisan.

In some embodiments, direct functionalization of 2-unsubstituted analogsof compounds of Formula (I) and (e.g., compounds of Formula (X)), forexample, with an alkyl halide, under basic conditions can be used toprovide the compounds of Formula (I) and (II).

In other embodiments, transition metal mediated cross coupling ofcompounds of Formula (XI) where A is a halogen can be used to preparecompounds of Formula (I).

In still other embodiments, compounds of Formula (I) can be prepared bydirect insertion into N1 of compounds of Formula (XII).

An exemplary synthesis of compounds of Formula (I) where X is —SO₂— or—S— can prepared by the scheme illustrated below. Compound 6 can beconverted by methods well known to those of skill in the art tocompounds of Formula (XI).

Compositions and Methods of Administration

The compositions provided herein contain therapeutically effectiveamounts of one or more of the compounds provided herein that are usefulin the prevention, treatment, or amelioration of one or more of thesymptoms of diseases or disorders described herein and a vehicle.Vehicles suitable for administration of the compounds provided hereininclude any such carriers known to those skilled in the art to besuitable for the particular mode of administration.

In addition, the compounds may be formulated as the sole activeingredient in the composition or may be combined with other activeingredients.

The compositions contain one or more compounds provided herein. Thecompounds are, in some embodiments, formulated into suitablepreparations such as solutions, suspensions, tablets, dispersibletablets, pills, capsules, powders, sustained release formulations orelixirs, for oral administration or in sterile solutions or suspensionsfor parenteral administration, as well as topical administration,transdermal administration, nasal inhalation, and oral inhalation vianebulizers, pressurized metered dose inhalers and dry powder inhalers.In some embodiments, the compounds described above are formulated intocompositions using techniques and procedures well known in the art (see,e.g., Ansel, Introduction to Pharmaceutical Dosage Forms, SeventhEdition (1999)).

In the compositions, effective concentrations of one or more compoundsor derivatives thereof is (are) mixed with a suitable vehicle. Thecompounds may be derivatized as the corresponding salts, esters, enolethers or esters, acetals, ketals, orthoesters, hemiacetals, hemiketals,acids, bases, solvates, ion-pairs, hydrates or prodrugs prior toformulation, as described above. The concentrations of the compounds inthe compositions are effective for delivery of an amount, uponadministration that treats, leads to prevention, or amelioration of oneor more of the symptoms of diseases or disorders described herein. Insome embodiments, the compositions are formulated for single dosageadministration. To formulate a composition, the weight fraction of acompound is dissolved, suspended, dispersed or otherwise mixed in aselected vehicle at an effective concentration such that the treatedcondition is relieved, prevented, or one or more symptoms areameliorated.

The active compound is included in the vehicle in an amount sufficientto exert a therapeutically useful effect in the absence of undesirableside effects on the patient treated. The therapeutically effectiveconcentration may be predicted empirically by testing the compounds inin vitro and in vivo systems well known to those of skill in the art andthen extrapolated therefrom for dosages for humans. Human doses are thentypically fine-tuned in clinical trials and titrated to response.

The concentration of active compound in the composition will depend onabsorption, inactivation and excretion rates of the active compound, thephysicochemical characteristics of the compound, the dosage schedule,and amount administered as well as other factors known to those of skillin the art. For example, the amount that is delivered is sufficient toameliorate one or more of the symptoms of diseases or disorders asdescribed herein.

In some embodiments, a therapeutically effective dosage should produce aserum concentration of active ingredient of from about 0.001 ng/ml toabout 1.0 ng/ml, 2-10 ng/ml, 11 to 50 ng/ml, 51-200 ng/ml, or about 200to 1000 ng/ml. The compositions, in other embodiments, should provide adosage of from about 0.0001 mg to about 70 mg of compound per kilogramof body weight per day. Dosage unit forms are prepared to provide fromabout 0.01 mg, 0.1 mg or 1 mg to about 500 mg, or about 1000 mg, and insome embodiments from about 10 mg to about 500 mg of the activeingredient or a combination of essential ingredients per dosage unitform.

The active ingredient may be administered at once, or may be dividedinto a number of smaller doses to be administered at intervals of time.It is understood that the precise dosage and duration of treatment is afunction of the disease being treated and may be determined empiricallyusing known testing protocols or by extrapolation from in vivo or invitro test data or subsequent clinical testing. It is to be noted thatconcentrations and dosage values may also vary with the severity of thecondition to be alleviated. It is to be further understood that for anyparticular subject, specific dosage regimens should be adjusted overtime according to the individual need and the professional judgment ofthe person administering or supervising the administration of thecompositions and that the concentration ranges set forth herein areexemplary only and are not intended to limit the scope or practice ofthe claimed compositions.

In instances in which the compounds exhibit insufficient solubility,methods for solubilizing compounds may be used such as use of liposomes,prodrugs, complexation/chelation, nanoparticles, or emulsions ortertiary templating. Such methods are known to those of skill in thisart, and include, but are not limited to, using co-solvents, such asdimethylsulfoxide (DMSO), using surfactants or surface modifiers, suchas TWEEN®, complexing agents such as cyclodextrin or dissolution byenhanced ionization (i.e., dissolving in aqueous sodium bicarbonate).Derivatives of the compounds, such as prodrugs of the compounds may alsobe used in formulating effective compositions.

Upon mixing or addition of the compound(s), the resulting mixture may bea solution, suspension, emulsion or the like. The form of the resultingmixture depends upon a number of factors, including the intended mode ofadministration and the solubility of the compound in the selectedvehicle. The effective concentration is sufficient for ameliorating thesymptoms of the disease, disorder or condition treated and may beempirically determined.

The compositions are provided for administration to humans and animalsin indication appropriate dosage forms, such as dry powder inhalers(DPIs), pressurized metered dose inhalers (pMDIs), nebulizers, tablets,capsules, pills, sublingual tapes/bioerodible strips, tablets orcapsules, powders, granules, lozenges, lotions, salves, suppositories,fast melts, transdermal patches or other transdermal applicationdevices/preparations, sterile parenteral solutions or suspensions, andoral solutions or suspensions, and oil-water emulsions containingsuitable quantities of the compounds or derivatives thereof. Thetherapeutically active compounds and derivatives thereof are, in someembodiments, formulated and administered in unit-dosage forms ormultiple-dosage forms. Unit-dose forms as used herein refer tophysically discrete units suitable for human and animal subjects andpackaged individually as is known in the art. Each unit-dose contains apredetermined quantity of the therapeutically active compound sufficientto produce the desired therapeutic effect, in association with therequired vehicle. Examples of unit-dose forms include ampoules andsyringes and individually packaged tablets or capsules. Unit-dose formsmay be administered in fractions or multiples thereof. A multiple-doseform is a plurality of identical unit-dosage forms packaged in a singlecontainer to be administered in segregated unit-dose form. Examples ofmultiple-dose forms include vials, bottles of tablets or capsules orbottles of pints or gallons. Hence, multiple dose form is a multiple ofunit-doses which are not segregated in packaging.

Liquid compositions can, for example, be prepared by dissolving,dispersing, or otherwise mixing an active compound as defined above andoptional adjuvants in a vehicle, such as, for example, water, saline,aqueous dextrose, glycerol, glycols, ethanol, and the like, to therebyform a solution or suspension, colloidal dispersion, emulsion orliposomal formulation. If desired, the composition to be administeredmay also contain minor amounts of nontoxic auxiliary substances such aswetting agents, emulsifying agents, solubilizing agents, pH bufferingagents and the like, for example, acetate, sodium citrate, cyclodextrinderivatives, sorbitan monolaurate, triethanolamine sodium acetate,triethanolamine oleate, and other such agents.

Actual methods of preparing such dosage forms are known, or will beapparent, to those skilled in this art; for example, see Remington'sPharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15thEdition, 1975 or later editions thereof.

Dosage forms or compositions containing active ingredient in the rangeof 0.005% to 100% with the balance made up from vehicle or carrier maybe prepared. Methods for preparation of these compositions are known tothose skilled in the art. The contemplated compositions may contain0.001%-100% active ingredient, in one embodiment 0.1-95%, in anotherembodiment 0.4-10%.

In certain embodiments, the compositions are lactose-free compositionscontaining excipients that are well known in the art and are listed, forexample, in the U.S. Pharmacopeia (USP) 25-NF20 (2002). In general,lactose-free compositions contain active ingredients, a binder/filler,and a lubricant in compatible amounts. Particular lactose-free dosageforms contain active ingredients, microcrystalline cellulose,pre-gelatinized starch, and magnesium stearate.

Further provided are anhydrous compositions and dosage forms includingactive ingredients, since water can facilitate the degradation of somecompounds. For example, the addition of water (e.g., 5%) is widelyaccepted as a means of simulating long-term storage in order todetermine characteristics such as shelf-life or the stability offormulations over time. See, e.g., Jens T. Carstensen, Drug Stability:Principles & Practice, 2d. Ed., Marcel Dekker, NY, N.Y., 1995, pp.379-80. In effect, water and heat accelerate the decomposition of somecompounds. Thus, the effect of water on a formulation can be of greatsignificance since moisture and/or humidity are commonly encounteredduring manufacture, handling, packaging, storage, shipment, and use offormulations.

Anhydrous compositions and dosage forms provided herein can be preparedusing anhydrous or low moisture containing ingredients and low moistureor low humidity conditions.

An anhydrous composition should be prepared and stored such that itsanhydrous nature is maintained. Accordingly, anhydrous compositions aregenerally packaged using materials known to prevent exposure to watersuch that they can be included in suitable formulary kits. Examples ofsuitable packaging include, but are not limited to, hermetically sealedfoils, plastics, unit dose containers (e.g., vials), blister packs, andstrip packs.

Oral dosage forms are either solid, gel or liquid. The solid dosageforms are tablets, capsules, granules, and bulk powders. Types of oraltablets include compressed, chewable lozenges and tablets which may beenteric-coated, sugar-coated or film-coated. Capsules may be hard orsoft gelatin capsules, while granules and powders may be provided innon-effervescent or effervescent form with the combination of otheringredients known to those skilled in the art.

In certain embodiments, the formulations are solid dosage forms such asfor example, capsules or tablets. The tablets, pills, capsules, trochesand the like can contain one or more of the following ingredients, orcompounds of a similar nature: a binder; a lubricant; a diluent; aglidant; a disintegrating agent; a coloring agent; a sweetening agent; aflavoring agent; a wetting agent; an enteric coating; a film coatingagent and modified release agent. Examples of binders includemicrocrystalline cellulose, methyl paraben, polyalkyleneoxides, gumtragacanth, glucose solution, acacia mucilage, gelatin solution,molasses, polyvinylpyrrolidine, povidone, crospovidones, sucrose andstarch and starch derivatives. Lubricants include talc, starch,magnesium/calcium stearate, lycopodium and stearic acid. Diluentsinclude, for example, lactose, sucrose, trehalose, lysine, leucine,lecithin, starch, kaolin, salt, mannitol and dicalcium phosphate.Glidants include, but are not limited to, colloidal silicon dioxide.Disintegrating agents include crosscarmellose sodium, sodium starchglycolate, alginic acid, corn starch, potato starch, bentonite,methylcellulose, agar and carboxymethylcellulose. Coloring agentsinclude, for example, any of the approved certified water soluble FD andC dyes, mixtures thereof; and water insoluble FD and C dyes suspended onalumina hydrate and advanced coloring or anti-forgery color/opalescentadditives known to those skilled in the art. Sweetening agents includesucrose, lactose, mannitol and artificial sweetening agents such assaccharin, and any number of spray dried flavors. Flavoring agentsinclude natural flavors extracted from plants such as fruits andsynthetic blends of compounds which produce a pleasant sensation or maskunpleasant taste, such as, but not limited to peppermint and methylsalicylate. Wetting agents include propylene glycol monostearate,sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylenelauryl ether. Enteric-coatings include fatty acids, fats, waxes,shellac, ammoniated shellac and cellulose acetate phthalates. Filmcoatings include hydroxyethylcellulose, sodium carboxymethylcellulose,polyethylene glycol 4000 and cellulose acetate phthalate. Modifiedrelease agents include polymers such as the Eudragit® series andcellulose esters.

The compound, or derivative thereof, can be provided in a compositionthat protects it from the acidic environment of the stomach. Forexample, the composition can be formulated in an enteric coating thatmaintains its integrity in the stomach and releases the active compoundin the intestine. The composition may also be formulated in combinationwith an antacid or other such ingredient.

When the dosage unit form is a capsule, it can contain, in addition tomaterial of the above type, a liquid carrier such as a fatty oil. Inaddition, dosage unit forms can contain various other materials whichmodify the physical form of the dosage unit, for example, coatings ofsugar and other enteric agents. The compounds can also be administeredas a component of an elixir, suspension, syrup, wafer, sprinkle, chewinggum or the like. A syrup may contain, in addition to the activecompounds, sucrose as a sweetening agent and certain preservatives, dyesand colorings and flavors.

The active materials can also be mixed with other active materials whichdo not impair the desired action, or with materials that supplement thedesired action. The active ingredient is a compound or derivativethereof as described herein. Higher concentrations, up to about 98% byweight of the active ingredient may be included.

In all embodiments, tablets and capsules formulations may be coated asknown by those of skill in the art in order to modify or sustaindissolution of the active ingredient. Thus, for example, they may becoated with a conventional enterically digestible coating, such asphenylsalicylate, waxes and cellulose acetate phthalate.

Liquid oral dosage forms include aqueous solutions, emulsions,suspensions, solutions and/or suspensions reconstituted fromnon-effervescent granules and effervescent preparations reconstitutedfrom effervescent granules. Aqueous solutions include, for example,elixirs and syrups. Emulsions are either oil-in-water or water-in-oil.

Elixirs are clear, sweetened, hydroalcoholic preparations. Vehicles usedin elixirs include solvents. Syrups are concentrated aqueous solutionsof a sugar, for example, sucrose, and may contain a preservative. Anemulsion is a two-phase system in which one liquid is dispersed in theform of small globules throughout another liquid. Carriers used inemulsions are non-aqueous liquids, emulsifying agents and preservatives.Suspensions use suspending agents and preservatives. Acceptablesubstances used in non-effervescent granules, to be reconstituted into aliquid oral dosage form, include diluents, sweeteners and wettingagents. Acceptable substances used in effervescent granules, to bereconstituted into a liquid oral dosage form, include organic acids anda source of carbon dioxide. Coloring and flavoring agents are used inall of the above dosage forms.

Solvents include glycerin, sorbitol, ethyl alcohol and syrup. Examplesof preservatives include glycerin, methyl and propylparaben, benzoicacid, sodium benzoate and alcohol. Examples of non-aqueous liquidsutilized in emulsions include mineral oil and cottonseed oil. Examplesof emulsifying agents include gelatin, acacia, tragacanth, bentonite,and surfactants such as polyoxyethylene sorbitan monooleate. Suspendingagents include sodium carboxymethylcellulose, pectin, tragacanth, Veegumand acacia. Sweetening agents include sucrose, syrups, glycerin andartificial sweetening agents such as saccharin. Wetting agents includepropylene glycol monostearate, sorbitan monooleate, diethylene glycolmonolaurate and polyoxyethylene lauryl ether. Organic acids includecitric and tartaric acid. Sources of carbon dioxide include sodiumbicarbonate and sodium carbonate. Coloring agents include any of theapproved certified water soluble FD and C dyes, and mixtures thereof.Flavoring agents include natural flavors extracted from plants suchfruits, and synthetic blends of compounds, which produce a pleasanttaste sensation.

For a solid dosage form, the solution or suspension, in for example,propylene carbonate, vegetable oils or triglycerides, is in someembodiments encapsulated in a gelatin capsule. Such solutions, and thepreparation and encapsulation thereof, are disclosed in U.S. Pat. Nos.4,328,245; 4,409,239; and 4,410,545. For a liquid dosage form, thesolution, e.g., for example, in a polyethylene glycol, may be dilutedwith a sufficient quantity of a liquid vehicle, e.g., water, to beeasily measured for administration.

Alternatively, liquid or semi-solid oral formulations may be prepared bydissolving or dispersing the active compound or salt in vegetable oils,glycols, triglycerides, propylene glycol esters (e.g., propylenecarbonate) and other such cardriers, and encapsulating these solutionsor suspensions in hard or soft gelatin capsule shells. Other usefulformulations include those set forth in U.S. Pat. Nos. RE 28,819 and4,358,603. Briefly, such formulations include, but are not limited to,those containing a compound provided herein, a dialkylated mono- orpolyalkylene glycol, including, but not limited to, 1,2-dimethoxyethane,diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether,polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethylether wherein 350, 550 and 750 refer to the approximate averagemolecular weight of the polyethylene glycol, and one or moreantioxidants, such as butylated hydroxytoluene (BHT), butylatedhydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone,hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malicacid, sorbitol, phosphoric acid, thiodipropionic acid and its esters,and dithiocarbamates.

Other formulations include, but are not limited to, aqueous alcoholicsolutions including an acetal. Alcohols used in these formulations areany water-miscible solvents having one or more hydroxyl groups,including, but not limited to, propylene glycol and ethanol. Acetalsinclude, but are not limited to, di(lower alkyl) acetals of lower alkylaldehydes such as acetaldehyde diethyl acetal.

Parenteral administration, in some embodiments characterized byinjection, either subcutaneously, intramuscularly or intravenously isalso contemplated herein. Injectables can be prepared in conventionalforms, either as liquid solutions or suspensions, solid forms suitablefor solution or suspension in liquid prior to injection, or asemulsions. The injectables, solutions and emulsions also contain one ormore excipients. Suitable excipients are, for example, water, saline,dextrose, glycerol or ethanol. In addition, if desired, the compositionsto be administered may also contain minor amounts of non-toxic auxiliarysubstances such as wetting or emulsifying agents, pH buffering agents,stabilizers, solubility enhancers, and other such agents, such as forexample, sodium acetate, sorbitan monolaurate, triethanolamine oleateand cyclodextrins.

Implantation of a slow-release or sustained-release system, such that aconstant level of dosage is maintained (see, e.g., U.S. Pat. No.3,710,795) is also contemplated herein. Briefly, a compound providedherein is dispersed in a solid inner matrix, e.g.,polymethylmethacrylate, polybutylmethacrylate, plasticized orunplasticized polyvinylchloride, plasticized nylon, plasticizedpolyethyleneterephthalate, natural rubber, polyisoprene,polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetatecopolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonatecopolymers, hydrophilic polymers such as hydrogels of esters of acrylicand methacrylic acid, collagen, cross-linked polyvinylalcohol andcross-linked partially hydrolyzed polyvinyl acetate, that is surroundedby an outer polymeric membrane, e.g., polyethylene, polypropylene,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers,ethylene/vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride,vinylchloride copolymers with vinyl acetate, vinylidene chloride,ethylene and propylene, ionomer polyethylene terephthalate, butyl rubberepichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer, andethylene/vinyloxyethanol copolymer, that is insoluble in body fluids.The compound diffuses through the outer polymeric membrane in a releaserate controlling step. The percentage of active compound contained insuch parenteral compositions is highly dependent on the specific naturethereof, as well as the activity of the compound and the needs of thesubject.

Parenteral administration of the compositions includes intravenous,subcutaneous and intramuscular administrations. Preparations forparenteral administration include sterile solutions ready for injection,sterile dry soluble products, such as lyophilized powders, ready to becombined with a solvent just prior to use, including hypodermic tablets,sterile suspensions ready for injection, sterile dry insoluble productsready to be combined with a vehicle just prior to use and sterileemulsions. The solutions may be either aqueous or nonaqueous.

If administered intravenously, suitable carriers include physiologicalsaline or phosphate buffered saline (PBS), and solutions containingthickening and solubilizing agents, such as glucose, polyethyleneglycol, and polypropylene glycol and mixtures thereof.

Vehicles used in parenteral preparations include aqueous vehicles,nonaqueous vehicles, antimicrobial agents, isotonic agents, buffers,antioxidants, local anesthetics, suspending and dispersing agents,emulsifying agents, sequestering or chelating agents and othersubstances.

Examples of aqueous vehicles include Sodium Chloride Injection, RingersInjection, Isotonic Dextrose Injection, Sterile Water Injection,Dextrose and Lactated Ringers Injection. Nonaqueous parenteral vehiclesinclude fixed oils of vegetable origin, cottonseed oil, corn oil, sesameoil and peanut oil. Antimicrobial agents in bacteriostatic orfungistatic concentrations must be added to parenteral preparationspackaged in multiple-dose containers which include phenols or cresols,mercurials, benzyl alcohol, chlorobutanol, methyl and propylp-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride andbenzethonium chloride. Isotonic agents include sodium chloride anddextrose. Buffers include phosphate and citrate. Antioxidants includesodium bisulfate. Local anesthetics include procaine hydrochloride.Suspending and dispersing agents include sodium carboxymethylcellulose,hydroxypropyl methylcellulose and polyvinylpyrrolidone. Emulsifyingagents include Polysorbate 80 (Tween® 80). A sequestering or chelatingagent of metal ions includes EDTA. Carriers also include ethyl alcohol,polyethylene glycol and propylene glycol for water miscible vehicles;and sodium hydroxide, hydrochloric acid, citric acid or lactic acid forpH adjustment.

The concentration of compound is adjusted so that an injection providesan effective amount to produce the desired pharmacological effect. Theexact dose depends on the age, weight, body surface area and conditionof the patient or animal as is known in the art.

The unit-dose parenteral preparations are packaged in an ampoule, a vialor a syringe with a needle. All preparations for parenteraladministration must be sterile, as is known and practiced in the art.

Illustratively, intravenous or intraarterial infusion of a sterileaqueous solution containing an active compound is an effective mode ofadministration. Another embodiment is a sterile aqueous or oily solutionor suspension containing an active material injected as necessary toproduce the desired pharmacological effect.

Injectables are designed for local and systemic administration. In someembodiments, a therapeutically effective dosage is formulated to containa concentration of at least about 0.01% w/w up to about 90% w/w or more,in certain embodiments more than 0.1% w/w of the active compound to thetreated tissue(s).

The compound may be suspended in micronized or other suitable form ormay be derivatized to produce a more soluble active product or toproduce a prodrug. The form of the resulting mixture depends upon anumber of factors, including the intended mode of administration and thesolubility of the compound in the selected carrier or vehicle. Theeffective concentration is sufficient for ameliorating the symptoms ofthe condition and may be empirically determined.

Active ingredients provided herein can be administered by controlledrelease means or by delivery devices that are well known to those ofordinary skill in the art. Examples include, but are not limited to,those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809;3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548;5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108;5,891,474; 5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830;6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981;6,376,461; 6,419,961; 6,589,548; 6,613,358; 6,699,500 and 6,740,634.Such dosage forms can be used to provide slow or controlled-release ofone or more active ingredients using, for example, hydroxypropylmethylcellulose, other polymer matrices, gels, permeable membranes, osmoticsystems, multilayer coatings, microparticles, liposomes, microspheres,or a combination thereof to provide the desired release profile invarying proportions. Suitable controlled-release formulations known tothose of ordinary skill in the art, including those described herein,can be readily selected for use with the active ingredients providedherein.

All controlled-release products have a common goal of improving drugtherapy over that achieved by their non-controlled counterparts.Ideally, the use of an optimally designed controlled-release preparationin medical treatment is characterized by a minimum of drug substancebeing employed to cure or control the condition in a minimum amount oftime. Advantages of controlled-release formulations include extendedactivity of the drug, reduced dosage frequency, and increased patientcompliance. In addition, controlled-release formulations can be used toaffect the time of onset of action or other characteristics, such asblood levels of the drug, and can thus affect the occurrence of side(e.g., adverse) effects.

Most controlled-release formulations are designed to initially releasean amount of drug (active ingredient) that promptly produces the desiredtherapeutic effect, and gradually and continually release of otheramounts of drug to maintain this level of therapeutic or prophylacticeffect over an extended period of time. In order to maintain thisconstant level of drug in the body, the drug must be released from thedosage form at a rate that will replace the amount of drug beingmetabolized and excreted from the body. Controlled-release of an activeingredient can be stimulated by various conditions including, but notlimited to, pH, temperature, enzymes, water, or other physiologicalconditions or compounds.

In certain embodiments, the agent may be administered using intravenousinfusion, an implantable osmotic pump, a transdermal patch, liposomes,or other modes of administration. In some embodiments, a pump may beused (see, Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwaldet al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574(1989)). In other embodiments, polymeric materials can be used. In otherembodiments, a controlled release system can be placed in proximity ofthe therapeutic target, i.e., thus requiring only a fraction of thesystemic dose (see, e.g., Goodson, Medical Applications of ControlledRelease, vol. 2, pp. 115-138 (1984)). In some embodiments, a controlledrelease device is introduced into a subject in proximity of the site ofinappropriate immune activation or a tumor. Other controlled releasesystems are discussed in the review by Langer (Science 249:1527-1533(1990)). The active ingredient can be dispersed in a solid inner matrix,e.g., polymethylmethacrylate, polybutylmethacrylate, plasticized orunplasticized polyvinylchloride, plasticized nylon, plasticizedpolyethyleneterephthalate, natural rubber, polyisoprene,polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetatecopolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonatecopolymers, hydrophilic polymers such as hydrogels of esters of acrylicand methacrylic acid, collagen, cross-linked polyvinylalcohol andcross-linked partially hydrolyzed polyvinyl acetate, that is surroundedby an outer polymeric membrane, e.g., polyethylene, polypropylene,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers,ethylene/vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride,vinylchloride copolymers with vinyl acetate, vinylidene chloride,ethylene and propylene, ionomer polyethylene terephthalate, butyl rubberepichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer, andethylene/vinyloxyethanol copolymer, that is insoluble in body fluids.The active ingredient then diffuses through the outer polymeric membranein a release rate controlling step. The percentage of active ingredientcontained in such parenteral compositions is highly dependent on thespecific nature thereof, as well as the needs of the subject.

Of interest herein are also lyophilized powders, which can bereconstituted for administration as solutions, emulsions and othermixtures. They may also be reconstituted and formulated as solids orgels.

The sterile, lyophilized powder is prepared by dissolving a compoundprovided herein, or a derivative thereof, in a suitable solvent. Thesolvent may contain an excipient which improves the stability or otherpharmacological component of the powder or reconstituted solution,prepared from the powder. Excipients that may be used include, but arenot limited to, an antioxidant, a buffer and a bulking agent. In someembodiments, the excipient is selected from dextrose, sorbitol,fructose, corn syrup, xylitol, glycerin, glucose, sucrose and othersuitable agent. The solvent may contain a buffer, such as citrate,sodium or potassium phosphate or other such buffer known to those ofskill in the art at, at about neutral pH. Subsequent sterile filtrationof the solution followed by lyophilization under standard conditionsknown to those of skill in the art provides the desired formulation. Insome embodiments, the resulting solution will be apportioned into vialsfor lyophilization. Each vial will contain a single dosage or multipledosages of the compound. The lyophilized powder can be stored underappropriate conditions, such as at about 4° C. to room temperature.

Reconstitution of this lyophilized powder with water for injectionprovides a formulation for use in parenteral administration. Forreconstitution, the lyophilized powder is added to sterile water orother suitable carrier. The precise amount depends upon the selectedcompound. Such amount can be empirically determined.

Topical mixtures are prepared as described for the local and systemicadministration. The resulting mixture may be a solution, suspension,emulsions or the like and are formulated as creams, gels, ointments,emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes,foams, aerosols, irrigations, sprays, suppositories, bandages, dermalpatches or any other formulations suitable for topical administration.

The compounds or derivatives thereof may be formulated as aerosols fortopical application, such as by inhalation (see, e.g., U.S. Pat. Nos.4,044,126, 4,414,209, and 4,364,923, which describe aerosols fordelivery of a steroid useful for treatment of inflammatory diseases,particularly asthma). These formulations for administration to therespiratory tract can be in the form of an aerosol or solution for anebulizer, or as a microfine powder for insufflation, alone or incombination with an inert carrier such as lactose. In such a case, theparticles of the formulation will, in some embodiments, have mass mediangeometric diameters of less than 5 microns, in other embodiments lessthan 10 microns.

Oral inhalation formulations of the compounds or derivatives suitablefor inhalation include metered dose inhalers, dry powder inhalers andliquid preparations for administration from a nebulizer or metered doseliquid dispensing system. For both metered dose inhalers and dry powderinhalers, a crystalline form of the compounds or derivatives is thepreferred physical form of the drug to confer longer product stability.

In addition to particle size reduction methods known to those skilled inthe art, crystalline particles of the compounds or derivatives can begenerated using supercritical fluid processing which offers significantadvantages in the production of such particles for inhalation deliveryby producing respirable particles of the desired size in a single step.(e.g., International Publication No. WO2005/025506). A controlledparticle size for the microcrystals can be selected to ensure that asignificant fraction of the compounds or derivatives is deposited in thelung. In some embodiments, these particles have a mass medianaerodynamic diameter of about 0.1 to about 10 microns, in otherembodiments, about 1 to about 5 microns and still other embodiments,about 1.2 to about 3 microns.

Inert and non-flammable HFA propellants are selected from HFA 134a(1,1,1,2-tetrafluoroethane) and HFA 227e(1,1,1,2,3,3,3-heptafluoropropane) and provided either alone or as aratio to match the density of crystal particles of the compounds orderivatives. A ratio is also selected to ensure that the productsuspension avoids detrimental sedimentation or cream (which canprecipitate irreversible agglomeration) and instead promote a looselyflocculated system, which is easily dispersed when shaken. Looselyfluctuated systems are well regarded to provide optimal stability forpMDI canisters. As a result of the formulation's properties, theformulation contained no ethanol and no surfactants/stabilizing agents.

The compounds may be formulated for local or topical application, suchas for topical application to the skin and mucous membranes, such as inthe eye, in the form of gels, creams, and lotions and for application tothe eye or for intracisternal or intraspinal application. Topicaladministration is contemplated for transdermal delivery and also foradministration to the eyes or mucosa, or for inhalation therapies. Nasalsolutions of the active compound alone or in combination with otherexcipients can also be administered.

For nasal administration, the preparation may contain an esterifiedphosphonate compound dissolved or suspended in a liquid carrier, inparticular, an aqueous carrier, for aerosol application. The carrier maycontain solubilizing or suspending agents such as propylene glycol,surfactants, absorption enhancers such as lecithin or cyclodextrin, orpreservatives.

Solutions, particularly those intended for ophthalmic use, may beformulated as 0.01%-10% isotonic solutions, pH about 5-7.4, withappropriate salts.

Other routes of administration, such as transdermal patches, includingiontophoretic and electrophoretic devices, and rectal administration,are also contemplated herein.

Transdermal patches, including iontophoretic and electrophoreticdevices, are well known to those of skill in the art. For example, suchpatches are disclosed in U.S. Pat. Nos. 6,267,983, 6,261,595, 6,256,533,6,167,301, 6,024,975, 6,010715, 5,985,317, 5,983,134, 5,948,433 and5,860,957.

For example, dosage forms for rectal administration are rectalsuppositories, capsules and tablets for systemic effect. Rectalsuppositories are used herein mean solid bodies for insertion into therectum which melt or soften at body temperature releasing one or morepharmacologically or therapeutically active ingredients. Substancesutilized in rectal suppositories are bases or vehicles and agents toraise the melting point. Examples of bases include cocoa butter(theobroma oil), glycerin-gelatin, carbowax (polyoxyethylene glycol) andappropriate mixtures of mono-, di- and triglycerides of fatty acids.Combinations of the various bases may be used. Agents to raise themelting point of suppositories include spermaceti and wax. Rectalsuppositories may be prepared either by the compressed method or bymolding. The weight of a rectal suppository, in one embodiment, is about2 to 3 gm. Tablets and capsules for rectal administration aremanufactured using the same substance and by the same methods as forformulations for oral administration.

The compounds provided herein, or derivatives thereof, may also beformulated to be targeted to a particular tissue, receptor, or otherarea of the body of the subject to be treated. Many such targetingmethods are well known to those of skill in the art. All such targetingmethods are contemplated herein for use in the instant compositions. Fornon-limiting examples of targeting methods, see, e.g., U.S. Pat. Nos.6,316,652, 6,274,552, 6,271,359, 6,253,872, 6,139,865, 6,131,570,6,120,751, 6,071,495, 6,060,082, 6,048,736, 6,039,975, 6,004,534,5,985,307, 5,972,366, 5,900,252, 5,840,674, 5,759,542 and 5,709,874.

In some embodiments, liposomal suspensions, including tissue-targetedliposomes, such as tumor-targeted liposomes, may also be suitable ascarriers. These may be prepared according to methods known to thoseskilled in the art. For example, liposome formulations may be preparedas described in U.S. Pat. No. 4,522,811. Briefly, liposomes such asmultilamellar vesicles (MLV's) may be formed by drying down phosphatidylcholine and phosphatidyl serine (7:3 molar ratio) on the inside of aflask. A solution of a compound provided herein in phosphate bufferedsaline lacking divalent cations (PBS) is added and the flask shakenuntil the lipid film is dispersed. The resulting vesicles are washed toremove unencapsulated compound, pelleted by centrifugation, and thenresuspended in PBS.

The compounds or derivatives may be packaged as articles of manufacturecontaining packaging material, a compound or derivative thereof providedherein, which is effective for treatment, prevention or amelioration ofone or more symptoms of the diseases or disorders, supra, within thepackaging material, and a label that indicates that the compound orcomposition or derivative thereof, is used for the treatment, preventionor amelioration of one or more symptoms of the diseases or disorders,supra.

The articles of manufacture provided herein contain packaging materials.Packaging materials for use in packaging products are well known tothose of skill in the art. See, e.g., U.S. Pat. Nos. 5,323,907,5,052,558 and 5,033,252. Examples of packaging materials include, butare not limited to, blister packs, bottles, tubes, inhalers, pumps,bags, vials, containers, syringes, bottles, and any packaging materialsuitable for a selected formulation and intended mode of administrationand treatment. A wide array of formulations of the compounds andcompositions provided herein are contemplated as are a variety oftreatments for any disease or disorder described herein.

Dosages

In human therapeutics, the physician will determine the dosage regimenthat is most appropriate according to a preventive or curative treatmentand according to the age, weight, stage of the disease and other factorsspecific to the subject to be treated. The compositions, in otherembodiments, should provide a dosage of from about 0.0001 mg to about 70mg of compound per kilogram of body weight per day. Dosage unit formsare prepared to provide from about 0.01 mg, 0.1 mg or 1 mg to about 500mg, or about 1000 mg, and in some embodiments from about 10 mg to about500 mg of the active ingredient or a combination of essentialingredients per dosage unit form.

The amount of active ingredient in the formulations provided herein,which will be effective in the prevention or treatment of a disorder orone or more symptoms thereof, will vary with the nature and severity ofthe disease or condition, and the route by which the active ingredientis administered. The frequency and dosage will also vary according tofactors specific for each subject depending on the specific therapy(e.g., therapeutic or prophylactic agents) administered, the severity ofthe disorder, disease, or condition, the route of administration, aswell as age, body, weight, response, and the past medical history of thesubject.

Exemplary doses of a formulation include milligram or microgram amountsof the active compound per kilogram of subject (e.g., from about 1micrograms per kilogram to about 50 milligrams per kilogram, from about10 micrograms per kilogram to about 30 milligrams per kilogram, fromabout 100 micrograms per kilogram to about 10 milligrams per kilogram,or from about 100 microgram per kilogram to about 5 milligrams perkilogram).

It may be necessary to use dosages of the active ingredient outside theranges disclosed herein in some cases, as will be apparent to those ofordinary skill in the art. Furthermore, it is noted that the clinicianor treating physician will know how and when to interrupt, adjust, orterminate therapy in conjunction with subject response.

Different therapeutically effective amounts may be applicable fordifferent diseases and conditions, as will be readily known by those ofordinary skill in the art. Similarly, amounts sufficient to prevent,manage, treat or ameliorate such disorders, but insufficient to cause,or sufficient to reduce, adverse effects associated with the compositionprovided herein are also encompassed by the above described dosageamounts and dose frequency schedules. Further, when a subject isadministered multiple dosages of a composition provided herein, not allof the dosages need be the same. For example, the dosage administered tothe subject may be increased to improve the prophylactic or therapeuticeffect of the composition or it may be decreased to reduce one or moreside effects that a particular subject is experiencing.

In certain embodiments, administration of the same formulation providedherein may be repeated and the administrations may be separated by atleast 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days,2 months, 75 days, 3 months, or 6 months.

Methods of Use of the Compounds and Compositions

Methods of treating, preventing, or ameliorating one or more symptoms ofdiseases including, for example, migraine, ALS, Alzheimer's disease,Parkinson's disease, extra-pyramidal disorders, depression, nausea,emesis, restless legs syndrome, insomnia, aggression, Huntington'sdisease, cardiopulmonary disease, fibrogenesis, pulmonary arterialhypertension, anxiety, drug addictions, dystonia, parasomnia orhyperprolactinemia are also provided herein. In practicing the methods,therapeutically effective amounts of the compounds or compositions,described herein, supra, are administered.

Also provided are methods for antagonizing receptors including 5-HT_(2B)receptors, adrenergic alpha_(1A), alpha_(1D), alpha_(2c), alpha_(2A) andalpha_(2B) receptors and D₂ and D₃ receptors using the compounds andcompositions, described herein. In practicing the methods,therapeutically effective amounts of the compounds or compositions,described herein, supra, are administered.

Also provided are methods for agonizing the 5-HT_(1D), 5-HT_(1A),5-HT_(1C) and D₂ receptors using the compounds and compositionsdescribed herein. In some embodiments, methods of selectively agonizingthe 5-HT_(1D) receptor over the 5-HT_(1B) receptor using the compoundsand compositions described herein are provided. In other embodiments,the compounds and compositions described herein selectively agonizes the5-HT_(1D) receptor over the 5-HT_(1B) receptor in a ratio of about 4:1.In still other embodiments, the compounds and compositions describedherein selectively agonizes the 5-HT_(1D) receptor over the 5-HT_(1B)receptor in a ratio of about 30:1. In some embodiments, methods ofselectively agonizing the 5-HT_(2C) receptor over the 5-HT_(2A) receptorusing the compounds and compositions described herein are provided.

Strong agonism of the 5-HT_(1B) receptor frequently leads to adversecardiovascular effects due to excessive vasoconstriction. Whileselective agonism as described above is preferred, also preferred isantagonism of adrenergic receptors such as, for example, alpha_(1A),alpha_(1D), alpha_(2A), alpha_(2B) and alpha_(2C) by migrainetherapeutics can reduce such vasoconstriction caused by strong 5-HT_(1B)agonism. In some embodiments, the compounds and compositions selectivelyagonizes the 5-HT_(1D) receptor over the 5-HT_(1B) receptor andantagonize one or more of adrenergic alpha_(1A) receptor, adrenergicalpha_(2A), receptor, or adrenergic alpha_(2B) receptor. In otherembodiments, the compounds and compositions agonizes one or more of5-HT_(1B) or 5-HT_(1D) receptor and antagonize one or more of adrenergicalpha_(1A) receptor, adrenergic alpha_(2A), receptor, or adrenergicalpha_(2B) receptor.

Strong agonism of the 5-HT_(2B) receptor frequently leads to undesirablecardiovascular complications such as valvular heart disease.Accordingly, selective agonism where the 5-HT_(2B) is not activated ishighly desirable.

In still other embodiments, methods of reducing agonism of dopaminereceptors when compared to agonism of dopamine receptors by otherergolines, such as, for example, dihydroergotamine using the compoundsand compositions described herein is provided herein. In someembodiments, the dopamine receptor is the D₂ receptor. In practicing themethods, therapeutically effective amounts of the compounds orcompositions are administered.

Combination Therapy

The compounds and compositions disclosed herein may also be used incombination with one or more other active ingredients. In certainembodiments, the compounds may be administered in combination, orsequentially, with another therapeutic agent. Such other therapeuticagents include those known for treatment, prevention, or amelioration ofone or more symptoms associated with migraine, ALS, Alzheimer's disease,Parkinson's disease, extra-pyramidal disorders, depression, nausea,emesis, restless legs syndrome, insomnia, aggression, Huntington'sdisease, cardiopulmonary disease, fibrogenesis, pulmonary arterialhypertension, anxiety, drug addictions, dystonia, parasomnia orhyperprolactinemia.

It should be understood that any suitable combination of the compoundsand compositions provided herein with one or more of the abovetherapeutic agents and optionally one or more further pharmacologicallyactive substances are considered to be within the scope of the presentdisclosure. In some embodiments, the compounds and compositions providedherein are administered prior to or subsequent to the one or moreadditional active ingredients.

It should also be understood that any suitable combination of thecompounds and compositions provided herein may be used with other agentsto agonize and or antagonize the receptors mentioned above.

Finally, it should be noted that there are alternative ways ofimplementing the present invention. Accordingly, the present embodimentsare to be considered as illustrative and not restrictive, and theinvention is not to be limited to the details given herein, but may bemodified within the scope and equivalents of the appended claims.

All publications and patents cited herein are incorporated by referencein their entirety.

EXAMPLES

The following examples are intended to be illustrative and not to belimiting.

Example 1 Synthesis of 2-Cycloropyl Terguride(3-((6aR,9S,10aR)-5-cyclopropyl-7-methyl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinolin-9-yl)-1,1-diethylurea)

A mixture of 1,2-dimethoxyethane (6 mL/mmol) and water (1.5 mL/mmol) wasflushed with argon and a mixture of 2-bromoterguride (160 mg, 0.38mmol), cyclopropylboronic acid (1.5 eq.) and K₃PO₄ (3.7 eq.) were thenadded. The mixture was flushed with argon for 10 min and thenPd(dppf)CI₂ (0.01 eq.) was added, and the resulting mixture was stirredat 90° C. overnight. Then, the mixture was cooled to room temperatureand diluted with EtOAc (2 mL/mmol) and water (2 mL/mmol). The mixturewas filtered and then the layers were separated. The organic phase waswashed with brine (10 mL/mmol) then dried over MgSO₄, filtered andconcentrated. The crude product was purified by preparative HPLC to give2-cyclopropylterguride (28 mg, 19% yield). APCI MS, m/z 381 [M+H]⁺,HPLC-MS (220 nm) 83% (AUC). ¹H-NMR (300 MHz, DMSO-d₆): δ 0.74-0.84 (2H,m); 0.87-0.97 (2H, m); 1.04 (6H, t, J=6.9 Hz); 1.38-1.54 (1H, m);1.92-2.08 (2H, m); 2.29-2.45 (4H, m); 2.53-2.65 (1H, m); 2.78-3.0 (2H,m); 3.1-3.3 (4H, m); 3.95-4.05 (1H, m); 5.55 (1H, d, J=6.6 Hz); 6.64-6.9(1H, d, J=6.9 Hz); 6.84-7.00 (2H, m); 10.25 (1H, s).

Example 2 Synthesis of 2-Bromomethysergide

Bromotrimethylsilane (6 eq.) was dissolved in dry DMSO (20 mL/mmol) andthe solution was stirred at rt for 15 min. Then methysergide maleate (1eq.) was added and the mixture was stirred at room temperature for 10min. The mixture was poured into ice-water (100 mL/mmol) and the pH wasadjusted to 8-9 with aq. ammonia and extracted with DCM (3×20 mL/mmol).The combined organic phase was washed with aq. Na₂S₂O₃ (2×10 mL/mmol)and brine (2×10 mL/mmol) then dried over MgSO₄, filtered andconcentrated. The crude product was purified by flash chromatography(DCM:MeOH, 0-10%) to give 2-bromomethysergide.

Example 3 Synthesis of 2-Cyclopropylmethysergide(6aR,9R)-5-cyclopropyl-N—((S)-1-hydroxybutan-2-yl)-4,7-dimethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide)

2-Cyclopropylmethysergide (25 mg, 7.6% yield) was synthesized from2-bromomethysergide (360 mg, 0.83 mmol) using the procedure ofExample 1. APCI MS, m/z 394 [M+H]⁺, HPLC-MS (220 nm) 92% (AUC). ¹H-NMR(300 MHz, DMSO-d₆): δ 0.56-0.65 (1H, m); 0.76-0.88 (4H, m); 0.95-1.3(2H, m); 1.26-1.41 (1H, m); 1.46-1.63 (1H, m); 1.85-1.96 (1H, m); 2.49(3H, s); 2.55-2.65 (1H, m); 2.96-3.08 (3H, m); 3.13-3.23 (1H, m);3.28-3.37 (1H, m); 3.45 (1H, dd, J¹=5.5 Hz, J²=14.9 Hz); 3.53-3.65 (1H,m); 3.74 (3H, s); 4.58 (1H, t, J=5.5 Hz); 6.42 (1H, d, J=4.3 Hz);7.00-7.08 (2H, m); 7.13-7.21 (1H, m); 7.84 (1H, d, J=8.4 Hz).

Example 4 Synthesis of 2-Bromodihydromethysergide

2-Bromodihydromethysergide was synthesized from dihydromethysergideusing the procedure of Example 2.

Example 5 Synthesis of 2-Cyclopropyldihydromethysergide(6aR,9R)-5-cyclopropyl-N—((S)-1-hydroxybutan-2-yl)-4,7-dimethyl-4,6,6a,7,8,9-hexahydroindolo[4,3-fg]quinoline-9-carboxamide)

2-Cyclopropyldihydromethysergide (105 mg, 30% yield) was synthesizedfrom 2-bromomethysergide (385 mg, 0.89 mmol) according to the procedureof Example 1. APCI MS, m/z 396 [M+H]⁺, HPLC-MS (220 nm) 99% (AUC).¹H-NMR (300 MHz, DMSO-d₆): δ 0.49-0.58 (1H, m); 0.84 (4H, t, J=7.6 Hz);0.93-1.01 (2H, m); 1.25-1.49 (2H, m); 1.51-1.66 (1H, m); 1.82-2.02 (2H,m); 2.13-2.3 (1H, m); 2.37 (3H, s); 2.41-2.47 (1H, m); 2.56-2.78 (3H,m); 2.88-3.02 (1H, m); 3.23-3.29 (1H, m); 3.34-3.43 (1H, m); 3.57-3.69(1H, m); 3.73 (3H, s); 4.61 (1H, t, J=5.6 Hz); 6.76 (1H, d, J=7.2 Hz);7.01 (1H, t, J=7.9 Hz); 7.11 (1H, d, J=8.3 Hz); 7.58 (1H, d, J=7.2 Hz).

Example 6 Synthesis of 10-Methoxyhydromethysergide((6aR,9R,10aS)—N—((S)-1-hydroxybutan-2-yl)-10a-methoxy-4,7-dimethyl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxamide)

Methysergide maleate (200 mg, 0.43 mmol) was dissolved in a mixture ofMeOH (11 mL/mmol) and cc. H₂SO₄ (0.35 mL/mmol) at −20° C. The solutionwas irradiated in a UV reactor using a mercury lamp under nitrogenatmosphere for 2 h at −20° C. The reaction mixture was diluted withwater (20 mL/mmol) and the pH was adjusted to 9-10 with IM aq. NaOH. Theaqueous solution was extracted with DCM (3×10 mL/mmol). The organicphase was dried over MgSO₄, filtered and concentrated. The crude productwas purified by preparative HPLC to give 10-methoxydihydromethysergide(20 mg, 12% yield). APCI MS, m/z 386 [M+H]⁺, HPLC-MS (220 nm) 91% (AUC).¹H-NMR (300 MHz, DMSO-d₆): δ 0.83 (3H, t, J=7.9 Hz); 1.24-1.38 (1H, m);1.47-1.64 (2H, m); 2.14-2.24 (2H, m); 2.31 (3H, s); 2.7-2.78 (1H, m);2.81 (3H, s); 2.84-3.06 (3H, m); 3.23-3.3 (1H, m); 3.34-3.43 (1H, m);3.58-3.68 (1H, m); 3.74 (3H, s); 4.61 (1H, t; J=5.5 Hz); 6.99 (1H, d,J=8.0 Hz); 7.11 (1H, d, J=8.0 Hz); 7.3 (1H, d, J=8.0 Hz); 7.65 (1H, d,J=8.6 Hz).

Example 7 Synthesis of 10-Methoxyhydromethylergometrine((6aR,9R,10aS)—N—((S)-1-hydroxybutan-2-yl)-10a-methoxy-4,7-dimethyl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxamide)

10-Methoxyhydromethylergometrine (41 mg, 12% yield) was synthesized frommethylergometrine (100 mg, 0.29 mmol) according to the procedure ofExample 6. APCI MS, m/z 372 [M+H]⁺, HPLC-MS (220 nm) 92% (AUC). ¹H-NMR(300 MHz, DMSO-d₆): δ 0.84 (3H, t, J=7.5 Hz); 1.2-1.36 (1H, m);1.47-1.65 (2H, m); 2.14-2.24 (2H, m); 2.31 (3H, s); 2.71-2.79 (1H, m);2.82 (3H, s); 2.86-3.07 (3H, m); 3.24-3.3 (1H, m); 3.35-3.43 (1H, m);3.57-3.69 (1H, m); 3.74 (3H, s); 4.62 (1H, m); 6.93-7.09 (3H, m); 7.25(1H, d, J=8.2 Hz); 7.64 (1H, d, J=8.1 Hz); 10.7 (1H, s).

What is claimed is:
 1. A compound of structural Formula (I):

or salts thereof, wherein: R₁ is hydrogen, alkyl, substituted alkyl,heteroalkyl, substituted heteroalkyl, aryl, substituted aryl, arylalkyl,substituted arylalkyl, halo, haloalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl, —S(O)_(j)R₁₀₁,—C(O)NR₁₀₂R₁₀₃ or —CO₂R₁₀₄; R₂ is alkyl, substituted alkyl, acyl,substituted acyl, halo, haloalkyl, heteroalkyl, substituted heteroalkyl,arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, substituted heteroarylalkyl, —NO₂, —N₃, —S(O)_(k)R₁₁₀,—OR₁₁₁, —NR₁₁₂R₁₁₃, —C(O)NR₁₁₄R₁₁₅, —OC(O)NR₁₁₆R₁₁₇, —CO₂R₁₁₈ or—OC(O)R₁₁₉; j and k are independently 0, 1 or 2; n is 0, 1, 2 or 3; R₃is hydrogen, alkyl, substituted alkyl, haloalkyl, heteroalkyl,substituted heteroalkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl orsubstituted heteroarylalkyl; R₄ and R₅ are independently hydrogen,alkyl, substituted alkyl, halo, haloalkyl, —OR₁₂₀, —OC(O)NR₁₂₁R₁₂₂,—OC(O)R₁₂₃ or together with the atoms to which they are attached form adouble bond; R₆ is hydrogen; R₇ is alkyl or substituted alkyl comprisingat least one fluorine atom; X is NR₈—; Z is —CH₂— or —NR₉—; a is 0; R₈is hydrogen; R₉, R₁₀₂-R₁₀₄ and R₁₁₁-R₁₂₃ are independently hydrogen,alkyl, substituted alkyl, acyl, substituted acyl, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, haloalkyl, heteroalkyl,substituted heteroalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl or substituted heteroarylalkyl; and R₁₀₁ and R₁₁₀ areindependently alkyl, substituted alkyl, acyl, substituted acyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, halo, haloalkyl,heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl or substituted heteroarylalkyl.
 2. Thecompound of claim 1 of structural formula (XIII):

wherein R₇ is

R₁₀ is substituted alkyl comprising at least one fluorine atom; Y is—S(O)_(k)R₁₁₇—OR₁₂ or —NR₁₃R₁₄; k is 0, 1 or 2; b is 1, 2, 3 or 4 R₁₁ isalkyl, substituted alkyl, acyl, substituted acyl, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, halo, haloalkyl, heteroalkyl,substituted heteroalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl or substituted heteroarylalkyl; and R₁₂-R₁₄ areindependently hydrogen, alkyl, substituted alkyl, acyl, substitutedacyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,haloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl or substituted heteroarylalkyl.
 3. Thecompound of claim 2, wherein: R₁ is hydrogen, alkyl, substituted alkyl,heteroalkyl or substituted heteroalkyl; R₂ is alkyl, substituted alkyl,acyl, halo, —OR₁₁₁, —C(O)NR₁₁₄R₁₁₅ or —CO₂R₁₁₈; n is 0 or 1; R₃ ishydrogen, alkyl, substituted alkyl, heteroalkyl or substitutedheteroalkyl; R₄ and R₅ are independently hydrogen, alkyl, substitutedalkyl, —OR₁₂₀ or together with the atoms to which they are attached forma double bond; b is 1 or 2; Y is —OR₁₂ or —NR₁₃R₁₄; and R₉, R₁₂-R₁₄,R₁₀₂-R₁₀₄ and R₁₁₁-R₁₂₃ are independently hydrogen, alkyl, substitutedalkyl, arylalkyl or substituted arylalkyl.
 4. The compound of claim 2,wherein: R₁ is hydrogen, alkyl, substituted alkyl, heteroalkyl orsubstituted heteroalkyl; R₂ is alkyl, substituted alkyl, acyl, halo,—OR₁₁₁, —C(O)NR₁₁₄R₁₁₅ or —CO₂R₁₁₈; n is 0 or 1; R₃ is hydrogen, alkyl,substituted alkyl, heteroalkyl or substituted heteroalkyl; R₄ and R₅ areindependently hydrogen, alkyl, substituted alkyl, —OR₁₂₀ or togetherwith the atoms to which they are attached form a double bond; b is 1 or2; Y is —OR₁₂ or —NR₁₃R₁₄; and R₉, R₁₂-R₁₄, R₁₀₂-R₁₀₄ and R₁₁₁-R₁₂₃ areindependently hydrogen, alkyl or arylalkyl.
 5. The compound of claim 2wherein: R₁ is hydrogen, halo, alkyl or substituted alkyl; R₃ is alkyl;and Y is —OR₁₂.
 6. The compound of claim 1 of structural Formula (VIII):

wherein: R₁ is alkyl or halo; R₃ is hydrogen, alkyl; R₄ and R₅ areindependently hydrogen, halo, —OR₁₂₀, —OC(O)NR₁₂₁R₁₂₂, —OC(O)R₁₂₃ ortogether with the atoms to which they are attached form a double bond;R₁₂₀ is hydrogen, methyl or alkyl; R₁₂₁ and R₁₂₂ are independentlyhydrogen or alkyl; and R₁₂₃ is alkyl.
 7. A composition comprising thecompound of claim 1 and a vehicle.
 8. The compound of claim 1, whereinR₁ is (C₁-C₄) alkyl or (C₁-C₄) substituted alkyl.
 9. The compound ofclaim 1, wherein R₁ is cyclopropyl, substituted cyclopropyl cyclobutylor substituted cyclobutyl.
 10. The compound of claim 1 having thestructure:


11. The compound of claim 1 having the structure:


12. The compound of claim 1 having the structure:


13. The compound of claim 1 having the structure:


14. The compound of claim 1 having the structure:


15. The compound of claim 1 having the structure:


16. The compound of claim 1 having the structure:


17. The compound of claim 1 having the structure:


18. The compound of claim 1 having the structure:


19. The compound of claim 1 having the structure:


20. The compound of claim 1 having the structure:


21. The compound of claim 1 having the structure:


22. The compound of claim 1 having the structure:


23. The compound of claim 1 having the structure:


24. The compound of claim 1 having the structure:


25. The compound of claim 1 having the structure:


26. The compound of claim 1 having the structure:


27. A compound having the structure:


28. A compound selected from the following:


29. A compound of structural formula (VIII):

or salts thereof, wherein: R₁ C₃-C₆ cycloalkyl or substituted C₃-C₆cycloalkyl; R₃ is hydrogen, alkyl, substituted alkyl, haloalkyl,heteroalkyl, substituted heteroalkyl, aryl, substituted aryl, arylalkyl,substituted arylalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl or substituted heteroarylalkyl; R₄ and R₅ areindependently hydrogen, alkyl, substituted alkyl, halo, haloalkyl,—OR₁₂₀, —OC(O)NR₁₂₁R₁₂₂, —OC(O)R₁₂₃ or together with the atoms to whichthey are attached form a double bond; R₆ is hydrogen; R₇ is alkyl orsubstituted alkyl; R₈ is hydrogen; and R₁₂₀-R₁₂₃ are independentlyhydrogen, alkyl, substituted alkyl, acyl, substituted acyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, haloalkyl,heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl or substituted heteroarylalkyl.
 30. Thecompound of claim 29, wherein the C₃-C₆ cycloalkyl is selected fromcyclopropyl, cyclobutyl, or cyclopentyl.
 31. The compound of claim 30,wherein the C₃-C₆ cycloalkyl is cyclopropyl.
 32. The compound of claim29 having the structure:


33. The compound of claim 29 having the structure:


34. The compound of claim 29 having the structure: